Compound with anti-hcv effect and method of its obtainment

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

 

The invention relates to the connection applicable for the prevention and treatment of viral infectious diseases, especially diseases of the liver caused by infection With hepatitis C virus (HCV), due to its inhibitory activity against HCV, which has a high degree of replication, the method of its production, intermediate connection, applicable to its receipt, and pharmaceutical compositions containing these compounds.

Currently, worldwide there are 100-200 million people infected with HCV, and it is estimated that there are over 2 million infected people in Japan. Approximately 50% of these patients the disease develops into chronic hepatitis, approximately 20% of these patients develop cirrhosis and liver cancer in thirty years or more after infection. Indicated that approximately 90% of cases of liver cancer caused by hepatitis C. In Japan, more than 20,000 patients die each year due to liver cancer, concomitant HCV infection.

HCV was discovered in 1989 as the main virus that causes non-a, non-b hepatitis due to transfusion. HCV is a RNA virus, which has a shell, and its genome consists of single-stranded (+)-RNA. It was classified as hepacivirus belonging to the Flavivirus family.

Because HCV "bypasses" the immune mechanism of the host of reasons, to the E. are still unclear, there are many cases in which results are achieved confirmed infection, even when the virus infected adult patients with advanced immune mechanism. The infection then develops into chronic hepatitis, cirrhosis and liver cancer, and it is known that there are a large number of patients with liver cancer is returned due to inflammation that occurs in non-cancer places, even if the cancer was removed surgically.

In line with this, there is a need to develop effective treatment of hepatitis C and, regardless of pathogenic or symptomatic of the ways that suppress inflammation through the use of anti-inflammatory drugs, there is a particularly large public the need to develop medicines that can weaken or eliminate HCV in the affected location of the liver.

Currently, treatment with interferon is the only known method that is effective in the elimination of HCV. However, interferon is effective only for about one third of all patients. The effectiveness of interferon against HCV, particularly genotype 1b is very low. Thus, it is desirable to develop a drug against HCV, which can be used instead of interest is Feron or in combination with him.

In recent years, although ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) was commercially available as a therapeutic drug for hepatitis C by concomitant use with interferon, its efficiency remains low, and the continuing search for new medicinal agents for the treatment of hepatitis C. in Addition, although attempts were made to eliminate the virus by increasing the immunity of the patient through the use of interferon agonists, agonists of Il-12 and so on, we discovered that neither was effective.

Since the cloning of the gene of HCV, although molecular biological analyses quickly progressed in relation to the mechanisms and functions of genes of viruses and functions of the various viral proteins, mechanisms, consisting of viral replication in host cells, confirmed infection, pathogenicity, and so forth, have not yet been fully explained. Currently no reliable test system for HCV infection using cultured cells. Thus, still in assessing the activity of drugs against HCV needed to apply the methods of analysis with the replacement of the virus with the use of other similar viruses.

In recent years, however, it became possible to observe the replication of HCV in vitro with the use of nonstructural h the particular domain of HCV. As a result of this drug against HCV can now easily assess an analysis of the replicon (V. Lohmann et al., ad., Science, 1999, Vol. 285, R-113, non-patent document 1). It is believed that the mechanism of replication of HCV RNA in this system is the same as the full replication of the RNA genome of HCV, which infected hepatocytes. Thus, we can say that this system is a system of analysis, which is based on the cells applicable for identification of compounds that inhibit HCV replication.

The authors of the present invention found that a number of compounds, which are described in international publication WO 98/56755 (patent document 1) and isolated from microorganisms such as the genus Aureobasidium, have a high degree of inhibitory activity for HCV replication, as determined by the above method of analysis of the replicon (application for Japan patent No. 2003-34056). These inhibitors have a high potential for use as therapeutic drugs for HCV. However, as this series of compounds derived from microorganisms, they have the disadvantage of difficulty of their synthesis or the synthesis of only limited derived from existing in nature connections.

Description of the invention

As a result of extensive studies to resolve the above problems, the author of this from the retene detected, the compounds of the present invention have a very high activity against the HCV replicon, have action, any abscopal growth HCV, have a weak cytotoxicity in vitro and are highly applicable as a preventive/therapeutic agents against HCV, while also found a way to obtain, which makes it easy to synthesize these compounds, thus led to the completion of the present invention.

The present invention is a search for connections that are applicable for the prevention and treatment of viral infections, especially diseases of the liver caused by infection With hepatitis C virus (HCV), due to its inhibitory activity against HCV with high replication rate, method of its production, intermediate compounds, applicable to its receipt, and pharmaceutical compositions containing such a compound.

The present invention relates to a method for producing compounds represented by formula (I):

(where a represents -(CH2)n-, where n is an integer 0-10;

Represents a-CH2-, -(C=O)-, -CH(OH)-, -CH(NH2)- or-C(=NOR)-, where R represents a hydrogen atom, an unbranched or branched alkyl group having 1-8 carbon atoms (which may be substituted amino what oppai, which may be mono - or tizamidine unbranched or branched alkyl group having 1-4 carbon atoms);

D represents -(CH2)m-R1where m is an integer of 0-10, and R' represents a hydrogen atom, an unbranched or branched alkyl group, an unbranched or branched alkylamino group, an unbranched or branched alkenylphenol group, cycloalkyl group, cycloalkenyl group, heterocyclic group which may be substituted, aryl group which may be substituted, a heteroaryl group which may be substituted, a group-OH (where X represents a hydrogen atom, an unbranched or branched alkyl group, an unbranched or branched alkylamino group, an unbranched or branched alkenylphenol group, cycloalkyl group or aryl group, which may be substituted), or halogen atom;

E represents a hydrogen atom or an unbranched or branched alkyl group;

G represents -(CH2)p-J, where p is an integer 0-4, and J represents a hydrogen atom, IT is a group, SH group, methylthiourea, carboxyl group, carbamoyl group, amino group, guanidinium, unbranched or branched alkyl group, cycloalkyl the group, unbranched or branched alkylamino group, an unbranched or branched alkenylphenol group, aryl group which may be substituted, a heterocyclic group which may be substituted, or a heteroaryl group which may be substituted;

communication Q represents a simple bond or double bond, and

R1, R2and R3may be the same or different and each represents a hydroxyl group, an amino group (which may be mono - or tizamidine unbranched or branched alkyl group having 1-4 carbon atoms), -OL, unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, or an unbranched or branched alkylamino group, where L represents an unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, or an unbranched or branched alkylamino group), its prodrug or pharmaceutically acceptable salt;

the method involves reacting the parent compound, represented by the following formula:

(where a, D and communication Q have the above meanings, and X and Y may be the same or different and each represents an unbranched or branched what th alkyl group or a protective group of carboxyl group) with ether α -amino acids represented by the following formula:

(where E and G have the abovementioned meanings and Z represents an unbranched or branched alkyl group or a protective group of carboxyl group) in the presence of a base agent and the combination with obtaining the compounds represented by the following formula:

(where a, D, E, G, the relation Q, X, Y, and Z values above), and then, if necessary, processing the specified connection with carrying out the hydrolysis, reduction, amination or amidation, hydroxykynurenine and/or conversion of ester to obtain the desired compounds of formula (I).

In addition, the present invention relates to a method for producing compounds represented by the following formula:

(where D and n have the meanings mentioned for the above formula (I), M1and M2may be the same or different and each represents an oxygen atom or sulfur atom and R and R' may be the same or different and each represents hydroxyamino group), including the interaction of the compounds represented by the following formula:

(where R and R' have the above meanings) with the compound represented by the following what armoloy:

(where D, n, M1and M2have the above values).

In addition, the present invention relates to a compound represented by the formula (I):

(where a, b, D, E, G, the relation Q, R1, R2and R3have the values listed for the above formula (I)), its prodrug or pharmaceutically acceptable salt.

In addition, the present invention relates to the compound of the above formula (I), its prodrug or pharmaceutically acceptable salts, where when n is equal to 6, D is an n-heptylene group and p is 1, then J is a group that is neither phenyl group (the phenyl group substituted by a group-OW in the u-position, where W represents a hydrogen atom, an unbranched or branched alkyl group, or an unbranched or branched alkenylphenol group)or 3-indolines group.

In addition, the present invention relates to the compound of the above formula (I), its prodrug or pharmaceutically acceptable salts, where when n is equal to 6, D is an n-heptylene group and p is 1, then J is a group that is neither phenyl group (the phenyl group substituted by a group-OW in the u-position, where W represents the atoms is hydrogen, unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, or an unbranched or branched alkylamino group)or 3-indolines group.

In addition, the present invention relates to a compound represented by the following formula:

(where R and R' may be the same or different and each represents hydroxyamino group).

In addition, the present invention relates to a compound represented by the following formula:

(where a, D, X and Y have the same meanings which are listed previously above).

In addition, the present invention relates to pharmaceutical compositions containing the compound of the above formula (I), its prodrug or pharmaceutically acceptable salt.

In addition, the present invention relates to the above pharmaceutical compositions for the prevention or treatment of viral infectious diseases.

In addition, the present invention relates to the aforementioned pharmaceutical composition, where viral infectious disease is an infectious disease caused by HCV.

In addition, the present invention relates to the aforementioned pharmaceutical composition, where infectious disease is called HCV, is hepatitis C, cirrhosis, fibrosis of the liver or liver cancer.

Since the compounds of the present invention have a very strong activity against HCV and actions, any abscopal growth HCV, and show weak cytotoxicity in vitro, pharmaceutical composition containing the compound of the present invention is highly applicable as a preventive/therapeutic agent against HCV.

The best way of carrying out the invention

In the present description unbranched or branched alkyl group refers to an unbranched or branched hydrocarbon groups having 1-12 carbon atoms, preferably an unbranched or branched hydrocarbon groups having 1-7 carbon atoms, if in the present description does not specifically mentioned. Examples of unbranched or branched alkyl groups include methyl group, ethyl group, through the group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, pentelow group and heptylene group. In addition, cycloalkyl group refers to cyclic hydrocarbon groups having 3-8 carbon atoms, examples of which include cyclopentyloxy group, tsiklogeksilnogo group and cycloheptyl group. Cycloalkenyl group belong to the cyclic uglevodorov the major groups, having 3-8 carbon atoms and containing at least one double bond, examples of them include cyclohexenyl group. In addition, unbranched or branched alkeneamine group refers to an unbranched or branched hydrocarbon groups having 2-8 carbon atoms and containing at least one double bond, and examples include vinyl group, 1-propenyloxy group, allyl group, 2-butenyloxy group and 2-ethynyl-2-butenyloxy group. Unbranched or branched alkyline group refers to an unbranched or branched hydrocarbon groups having 2-8 carbon atoms and containing at least one triple bond, examples of them include etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 3-butenyloxy group, 2-pantanillo group, 3-pantanillo group, 4-pantanillo group, 2-hexylamino group, 4-hexylamino group, 2-decimalno group, 6,6-dimethylheptyl-2,4-Dien-1-ilen group.

In addition, the heterocyclic group described in the present description, refers to a 4 to 6 membered monocyclic or 7-10-membered bicyclic group (preferably monocyclic group), which contains as ring members 1-4 (and, preferably, 1 or 2) heteroatoms independently selected from nitrogen atom,sulfur atom and oxygen atom, and which may have at least one double bond, and specific examples include groups formed from Piran, research, tetrahydrofuran, dihydrofuran, tetrahydropyran, dihydropyran, 1,3-dioxane, piperazine, piperidine and thiomorpholine.

Aryl groups described in the present description, refers to an aromatic monocyclic or polycyclic hydrocarbon group, specific examples include groups formed from benzene, naphthalene, anthracene and fluorene.

Heteroaryl groups described in the present description, refers to a 4 to 6 membered monocyclic or 7-10-membered bicyclic aromatic group (preferably monocyclic group containing, as ring members 1-4 (and, preferably, 1 or 2) heteroatoms independently selected from nitrogen atom, sulfur atom and oxygen atom, and specific examples include groups formed from furan, thiophene, pyrrole, pyrazole, pyridine, thiazole, imidazole, pyrimidine, indole, quinoline, oxazole, isoxazol, pyrazine, triazole, thiadiazole, tetrazole and pyrazole.

Kalkilya group described in the present description, refer to the above unbranched or branched alkyl groups substituted by the above aryl groups, and specific examples include benzyl g is the SCP and fenetylline group.

Heteroallyl group described in the present description, refers to the above unbranched or branched alkyl groups substituted by the above-mentioned heteroaryl groups.

Acyl group specified in the present description, refers to the above unbranched or branched alkyl, aryl, heteroaryl or heterocyclyl groups that are linked through a carbonyl group.

The term "may be substituted"indicated in the present description, refers to a group described this way, which is substituted by such a group, as unbranched or branched alkyl group, an unbranched or branched alkoxygroup, unbranched or branched Alchemilla group, an unbranched or branched alkenylacyl, unbranched or branched Alchemilla group, an unbranched or branched alkyloxy, cycloalkyl group, cycloalkylation, cyano, a nitro-group, triptorelin group, tripterocarpa, halogen atom, aryl group, alloctype, heteroaryl group, heteroanalogues, kalkilya group, oralchroma, amino group (which may be mono - or disubstituted unbranched or branched alkyl group), an acyl group, an unbranched or did the run alkylsulfonyl group, carnemolla group, an unbranched or branched allylthiourea, a carboxyl group, an unbranched or branched alkylcarboxylic group, formyl group or aminosulfonyl group, unless otherwise stated in the present invention. Aryl and heteroaryl part in which these substituents groups can be optionally mono-, di - or tizamidine a halogen atom, an unbranched or branched alkyl group, an unbranched or branched alkoxygroup, unbranched or branched alkenylphenol group, an unbranched or branched alkenylacyl, unbranched or branched alkenylphenol group, an unbranched or branched alkyloxy, cycloalkyl group, cycloalkylcarbonyl, a cyano, a nitro-group, triptorelin group, cryptomaterial, aryl group, arroceros, heteroaryl group, aranceles group, aralkylamines, amino group which may be mono - or disubstituted unbranched or branched alkyl group; acyl group, unbranched or branched alkylsulfonyl group, an unbranched or branched alkoxygroup, carbamoyl group, an unbranched or branched alkylthiol, a carboxyl group,an unbranched or branched alkylcarboxylic group, formyl group or aminosulfonyl group.

The protective group described in the present description, refers to a group to protect reactive functional group from undesired chemical reactions, which can be easily removed after completion of the reaction. Protective groups vary according to the type of functional group that should be protected, and in the case of protection of the hydroxyl group can be used preferably, for example, groups such as tert-butyldiphenylsilyl group, tetrahydropyranyl group, methoxymethyl group, benzyl group, trimethylsilyl group, p-methoxybenzyl group or tert-butyldimethylsilyl group. In defense of a carboxyl group, you can apply various protective groups, for example, described in "Protective Groups in Organic Synthesis", the 3rdedition (John Wiley & Sons, Inc., 1999) or "Organic Synthesis Experimental Method Handbook" (Maruzen, 1990). As a protective group of carboxyl group can be applied, for example, methyl group, ethyl group, tert-boutelou group, allyl group, phenyl group, benzyl group and various substituted silyl groups such as trimethylsilyl and triethylsilyl).

The prodrug described in this invention, refers to a derivative of the compounds of formula (I)which has been chemically modified so that the button it was able to turn into a compound of formula (I) or its pharmaceutically acceptable salt or in physiological conditions, or solvolysis after administration as pharmaceutical agents. Although the prodrug may be inactive when administered to a patient, it is present in the body after conversion to the active compound of the formula (I). Examples of prodrugs include compounds that undergo With1-6-alkyl esterification With1-6-alkenylphenol esterification With6-10-aryl esterification With1-6-alkyloxy-C1-6-alkyl esterification (formula below) or (C1-6-hydroxyalkyl etherification (formula below) of a part of the carboxylic acids of this connection.

In addition, the term "treatment"described in the present description, include the elimination or weakening of HCV, inhibition of further spread of HCV and relieving symptoms caused by HCV infection, the introduction of the pharmaceutical compositions of the present invention to a subject. Examples of symptoms caused by HCV infection include hepatitis C, cirrhosis, liver fibrosis and liver cancer.

In the future presents a detailed description of the compounds of the present invention.

Although the compound of the present invention is a compound represented by the above formula (I), its prodrug or pharmaceutically acceptable salt, it preferably is a compound, pre is raised by the above formula (I), in which case, when n is equal to 6, D is an n-heptylene group and p is 1, then J is a group that is neither phenyl group (the phenyl group substituted by a group-OW in the u-position, where W represents a hydrogen atom, an unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, or an unbranched or branched alkenylphenol group)or 3-indolines group.

In the compound represented by formula (I) of the present invention, And represents -(CH2)n-, where n is an integer from 0 to 10, preferably an integer of 2-8, and more preferably an integer of 4-8.

In addition, the compound represented by formula (I), although there is a -(C=O)-, -CH(OH)-, -CH(NH2)- or-C(=NOR)-, preferably represents -(C=O)- or-CH(OH)-.

In addition, the compound represented by formula (I), D represents -(CH2)m-R', where m is an integer of 1-10, preferably, an integer of 3-8. In addition, while R' represents a hydrogen atom, an unbranched or branched alkyl group, cycloalkyl group, cycloalkenyl group, an unbranched or branched alkylamino group, an unbranched or branched alkenylphenol group, heterocyclic group, which may be alsenoy, aryl group which may be substituted, a heteroaryl group which may be substituted, a group-OH (where X represents a hydrogen atom, an unbranched or branched alkyl group or a protective group of carboxyl group) or a halogen atom, R' represents preferably a hydrogen atom, an unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, cycloalkyl group or aryl group which may be substituted (and, particularly preferably phenyl group).

D is particularly preferably n-pentelow group, n-hexoloy group, n-heptylene group, n-aktiline group, n-pentanediol group or 2-etylhexyl group.

In addition, in the compound of formula (I), while E represents a hydrogen atom or an unbranched or branched alkyl group, E preferably represents a hydrogen atom.

In addition, in the compound of formula (I), while G represents -(CH2)p-J, where p is an integer 0-4, preferably, p is an integer from 0 to 2, particularly preferably 1. In addition, while J represents a hydrogen atom, IT is a group, SH group, methylthiourea, carboxyl group, carbamoyl group, amino group, guanidinium, unbranched or razvetvlenno the Yu alkyl group, cycloalkyl group, an unbranched or branched alkylamino group, an unbranched or branched alkenylphenol group, aryl group which may be substituted, a heterocyclic group which may be substituted, or a heteroaryl group which may be substituted, J preferably represents an aryl group which may be substituted, and more preferably, phenyl group (particularly preferably phenyl group which may be substituted in p-position). In addition, the aryl group which may be mono-, di - or tizamidine group selected from aryl groups, alloctype, aristocraty, killingray, aralkylated, heteroaryl group, aranceles group, heterocyclic group, geterotsiklicheskikh (aryl, heteroaryl or heterocyclic portion of these aryl, aryloxy, aaltio, arylamino, Uralkali, heteroaryl, kalkilya, heterocyclic and geterotsiklicheskikh can be optionally mono-, di - or tizamidine group selected from unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, an unbranched or branched alkenylphenol group, an unbranched or branched alkoxygroup, unbranched or razvetvlenno is alkyloxy, unbranched or branched alkyloxy, cycloalkylcarbonyl, triptorelin group, ceanography, halogen atom, nitro group, amino group which may be mono - or disubstituted unbranched or branched alkyl group, acyl group, an unbranched or branched alkylsulfonyl group, carbamoyl group, an unbranched or branched alkylthiol, a carboxyl group, an unbranched or branched alkylcarboxylic group, formyl group, aminosulfonyl group which may be mono - or disubstituted unbranched or branched alkyl group etc), unbranched or branched alkyl group, an unbranched or branched alkenylphenol group, an unbranched or branched alkenylphenol group, an unbranched or branched alkoxygroup (which may be substituted amino group which may be mono - or disubstituted unbranched or branched alkyl group; heteroanalogues or heterocyclic group), an unbranched or branched alkenylacyl, unbranched or branched alkyloxy (which may be substituted by dialkylamino), cycloalkylcarbonyl, triptorelin group, cryptometer, ceanography of halogen atom, nitro, amino which may be mono - or disubstituted unbranched or branched alkyl group, aminoalkyl group (which may be substituted aracelikarsaalyna group), guanidinium, killingray, sidegroup, acyl group, an unbranched or branched alkylsulfonyl group, an unbranched or branched alkylsulfonamides, carbamoyl group, an unbranched or branched allylthiourea, a carboxyl group, an unbranched or branched alkylcarboxylic, unbranched or branched alkylcarboxylic group, formyl group, etc.

Preferred examples of G include aracelio group which may be substituted, and especially benzyl group which may be substituted, and particularly preferred example is a benzyl group which is substituted in p-position.

In addition, the compound represented by formula (I), R1, R2and R3may be the same or different and each represents a hydroxyl group, an amino group (which may be mono - or disubstituted unbranched or branched alkyl group having 1-4 carbon atoms), -OL, unbranched or branched alkyl group, an unbranched or branched ALK is niloy group, or an unbranched or branched alkylamino group.

Especially preferred example of R1, R2and R3is a hydroxyl group.

The following are preferred examples of the compounds represented by formula (I) of the present invention.

Of the compounds represented by formula (I), particularly preferred are compounds(15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (33), (38), (39), (40), (41), (42), (43), (44), (45), (48), (49), (50), (51), (52) and (62).

In addition, the present invention relates to a method for producing compounds represented by formula (I):

(where a, b, D, E, G, R1, R2and R3have the same meanings which are listed above), its prodrug or pharmaceutically acceptable salt:

contains the interaction of the starting compound represented by the formula:

(where a and D have the same meanings which are listed above, and X and Y may be the same or different and each represents an unbranched or branched alkyl group) with ether α-amino acids represented by the shape of the nd:

(where E and G have the same meanings which are listed above, and Z represents an unbranched or branched alkyl group or a protective group of carboxyl group) in the presence of a base agent and the combination with obtaining the compound represented by the formula:

(where a, D, E, G, X, Y and Z have the same meanings which are listed above) and then, if necessary, treatment of this compound for carrying out the hydrolysis, reduction, amination or amidation, hydroxykynurenine and/or conversion of the ester to obtain the desired compound of formula (I).

Below is illustrated an example method for the synthesis of compounds represented by formula (I) of the present invention, using the following scheme of reactions.

A common way of obtaining 1

In the above formulas, each of the symbols has the same values as the values shown in the above formula (I), and each of P, P' and P" represents hydroxyamino group. The original connection in the form of compound 1 can be synthesized according to the method described in literature (J. Org. Chem. 1989, 45, 5522, B.E. Marron, et al.).

Stage 1-1

After the interaction of compound 1 with regenerating agent such as bis-(2-methoxyethoxy)aluminiumtrihydrate Il is aluminosilicate, in a solvent such as various ethers such as diethyl ether, tetrahydrofuran or dioxane, or benzene, toluene or cyclohexane, or a mixture of such solvents, at room temperature or with cooling, preferably at a temperature below the temperature of the ice, compound 2 can be obtained by treatment with iodine under cooling, preferably at a temperature of -78°C.

Stage 1-2

Compound 2 is then subjected to interaction with dihydropyran in a solvent such as diethyl ether, toluene, cyclohexane, methylene chloride, chloroform, 1,2-dichloroethane or ethyl acetate or a mixture of such solvents, in the presence of catalytic amount of acid, such as para-toluensulfonate pyridinium, toluensulfonate acid, methanesulfonate acid, acetic acid, triperoxonane acid or diluted hydrochloric acid, either at room temperature or under cooling, preferably at a temperature below the temperature of the ice, while receiving the connection 3.

Stage 1-3

The connection 3 is subjected to interaction with a strong base such as tert-utility, n-utility or second-utility, in a solvent such as various ethers such as diethyl ether, tetrahydrofuran or dioxane, or benzene, toluene or cyclohexane, or a mixture of such solvent is th, at room temperature or under cooling, preferably at a temperature of -78°C, followed by the addition of formaldehyde and providing opportunities for interaction of the mixture under cooling, preferably at a temperature below the temperature of the ice, getting connections 4.

Stage 1-4

Compound 4 is subjected to interaction with tert-butyldiphenylchlorosilane in a solvent such as N,N-dimethylformamide, tetrahydrofuran, methylene chloride or chloroform, or a mixture of such solvents, in the presence of a base such as imidazole, trimethylamine or pyridine, either at room temperature or under cooling, preferably at a temperature below the temperature of the ice, getting connection 5.

Stage 1-5

Compound 5 is subjected to interaction in various alcohol solvents such as ethanol, methanol or propanol, in the presence of catalytic amount of acid, such as para-toluensulfonate pyridinium, toluensulfonate acid, methanesulfonate acid, acetic acid, triperoxonane acid or dilute hydrochloric acid at room temperature or under heating, preferably under heating by boiling under reflux, to obtain compound 6.

Stage 1-6

The connection 6 is subjected to interaction with the peroxide is m, such as tert-butylhydroperoxide or cumonherface, in a solvent such as methylene chloride or chloroform, or a mixture of such solvents, in the presence of a Lewis acid such as tetraisopropoxide titanium or tetrabutoxide titanium, and L-(+)-diethyltartrate, L-(+)-dipropylacetate, D-(-)-diethyltartrate or D-(-)-dipropylacetate at room temperature or under cooling, preferably with cooling, to obtain compound 7.

Stage 1-7

After gidrometeorologia (such as gidroksilirovanii or hydroporinae) triple bond compounds represented by the formula:

having the desired chain (-(CH2)n-) and group D, which is synthesized according to the General method of obtaining 2, which will be described later, vinylecarbazole received by Parametrierung (using, for example, Grignard reagent and dialkylzinc), is subjected to the interaction with compound 7 in a solvent such as various ethers such as diethyl ether, tetrahydrofuran or dioxane, or benzene, toluene or cyclohexane, or a mixture of such solvents, at room temperature or under cooling, preferably at a temperature of -78°With connection 8.

Stage 1-8

Compound 8 is subjected to interaction with 2,2-dimethoxypropane Il is acetone and the solvent, such as diethyl ether, toluene, hexane, methylene chloride, chloroform or 1,2-dichloroethane, or a mixture of such solvents, in the presence of catalytic amount of acid, such as para-toluensulfonate pyridinium, toluensulfonate acid, methanesulfonate acid, acetic acid, triperoxonane acid, hydrochloric acid or sulfuric acid, at room temperature or under cooling, preferably at room temperature, to obtain compound (9).

Stage 1-9

The connection 9 is subjected to interaction in a solvent such as diethyl ether, tetrahydrofuran, hexane, methylene chloride or chloroform, or a mixture of such solvents, in the presence of tetrabutylammonium fluoride, hydrofluoric acid, acetic acid or dilute hydrochloric acid, and so forth and at room temperature or under cooling with connection 10.

Stage 1-10

The connection 10 is subjected to oxidation reaction with the use of peroxide of manganese, nitric acid or the oxidation method of Jones and so on, thus obtaining the corresponding dicarboxylic acid. In the alternative case, the connection 10 is subjected to oxidation using potassium permanganate oxidation method in Turn, the oxidation method according to Collins or oxidation of TAMRA and so on with getting to the corresponding dialdehyde. Preferably, after the interaction, the connection 10 in a solvent such as methylene chloride or chloroform and in the presence of oxalicacid and dimethyl sulfoxide, under cooling, preferably at -78°With, it is treated with base, such as triethylamine, to obtain the dialdehyde. The resulting product can then be turned into a dicarboxylic acid with an oxidant such as potassium permanganate, sodium chlorite or chromic acid. Dicarboxylic acid, preferably, is produced by contact with an aqueous solution of sodium chlorite and sodium dihydrophosphate 2-methyl-2-propanol and 2-methyl-2-butene at room temperature or under cooling, preferably with cooling. The resulting product is then subjected to interaction with di-tert-butylacetate N,N-dimethylformamide or with tert-butyl-2,2,2-trichloroacetimidate in a solvent such as N,N-dimethylformamide, diethyl ether, tetrahydrofuran, hexane, methylene chloride or chloroform, a mixture of such solvents, or in the absence of solvent at room temperature or under heating to obtain compound (11).

Stage 1-11

The connection 11 is subjected to interaction in a solvent such as tetrahydrofuran or dioxane or a mixture of such solvents, in the presence of water and acid, such as para-toluensulfonate pyridinium, methansulfonate to the slot or acetic acid, at room temperature or under cooling, preferably at room temperature, to obtain compound 12.

Stage 1-12

Compound 12 can be converted to the corresponding monocarboxylic acid by the oxidation reaction with the use of peroxide of manganese, nitric acid or reagent Jones and so on. Preferably, the connection 12 is subjected to interaction with Jones reagent in acetone at room temperature or under cooling, preferably with cooling, to obtain compound 13.

Stage 1-13

Reagent combinations, such as hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea, water-soluble carbodiimide hydrochloride (WSC-HCl) or 1-hydroxybenzotriazole (HOBt), interacts with the connection 13 and the hydrochloride tert-butyl ether α-amino acid in a solvent such as N,N-dimethylformamide, tetrahydrofuran, diethyl ether, methylene chloride or chloroform, or a mixture of such solvents, in the presence of a base, such as N,N-diisopropylethylamine, triethylamine, pyridine or 4-N,N-dimethylaminopyridine, at room temperature or under cooling, preferably at room temperature, to obtain the compound 14-a, which is one type of compounds of formula (I).

Stage 1-14

The connection 14 And is subjected to interaction in the solvent, t is lump as ethyl ether, tetrahydrofuran, dioxane, hexane, methylene chloride, chloroform, ethyl acetate, or water or a mixture of such solvents, in the presence or absence of anisole in the presence of acid, such as methanesulfonate acid, acetic acid, triperoxonane acid or dilute hydrochloric acid at room temperature or under cooling, preferably at room temperature, to obtain compound 14, which is one type of compounds of formula (I).

The desired compound of formula (I) of the present invention other than the above compound 14 and compound 14 In, get with the use of compound 14-a or compound 14 as a source of product and process for hydrolysis, reduction, amination or amidation, hydroxykynurenine and/or transformation of the ether, if necessary. In addition, the compound of formula (I), in which the relationship Q represents a simple bond, can be obtained by hydrogenation of compound 14-a or connection 14-In in a solvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran, in the presence of a catalyst such as palladium-on-charcoal, palladium hydroxide, Raney Nickel or palladium oxide, at room temperature or under conditions of heating.

The present invention relates also to a method for the connection shown is of the formula:

(where D and n have the same meanings which are listed above, M1and M2may be the same or different and each represents an oxygen atom or a sulfur atom, and P and P' may be the same or different and each represents hydroxyamino group), which is an intermediate compound useful for the synthesis of compounds of formula (I), including the interaction of the compounds represented by the formula:

(where P and P' have the same meanings which are listed above), with the compound represented by the formula:

(where D, n, M1and M2have the same meanings which are listed above). This method is way stage 1-7 in the above General method of obtaining 1.

Below is explained a method of obtaining connection:

which is one of the intermediate compounds for the synthesis of the above compounds of formula (I), using the following scheme of reactions.

A common way to obtain 2

Stage 2-1

Reagent combinations, such as hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea, water-soluble carbodiimide hydrochloride (WSC-HCl) or 1-hydroxybenzotriazole (HOBt), interacts with the the group with the end of the triple bond and the desired circuit While ((CH2)n-), and hydrochloride of N,O-dimethylhydroxylamine in a solvent such as diethyl ether, tetrahydrofuran, dioxane, hexane, methylene chloride, chloroform or ethyl acetate or a mixture of such solvents, in the presence of a base, such as N,N-diisopropylethylamine, triethylamine, pyridine or 4-N,N-dimethylaminopyridine at room temperature to obtain compound b.

Stage 2-2

Compound b obtained in the above stage, interacts with the Grignard reagent or alkyllithium reagent with the desired group D, in a solvent such as diethyl ether, tetrahydrofuran, dioxane or hexane or a mixture of such solvents, at room temperature or under cooling, preferably with cooling, to obtain the connection, in which was introduced the group D.

Stage 2-3

The connection obtained in the above stage, is subjected to the interaction with ethylene glycol with azeotropic removal of water, which is formed by heating in a solvent such as benzene, toluene or 1,2-dichloroethane, and in the presence of acid, such as para-toluensulfonate pyridinium, para-toluensulfonate acid, methanesulfonate acid or acetic acid, to obtain the compound d.

Compound d obtained here, you can apply the stages 1-7 of the common way obtain 1, which shows how to obtain the above compound (I). It should be noted that connection, equivalent to a compound d, which M1and/or M2represent sulfur atoms, can be obtained by a method well known to the average expert in the field.

The connection, which is the starting compound for the synthesis of compounds of the above formula (I) and represented by the formula:

can be synthesized by the method known to the person skilled in the art, or one of the following schemes of the reactions of the common way obtain 3-5.

A common method of obtaining 3

In the above formulas, R"' represents a protective group of carboxyl group, R"represents a protective group of amino group, and M represents an unbranched or branched alkyl group, an unbranched or branched alkylamino group, an unbranched or branched alkenylphenol group or cycloalkyl group.

Stage 3-1

Connection CENTURIES can be obtained by protection of the connection AA protective group of amino group, such as acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl. Reaction conditions at this time is appropriately selected depending on the IPA protective group R"".

Stage 3-2

The connection of the SS can be obtained by the interaction of the compounds CENTURIES with M substituted with halogen or leaving group, such as methanesulfonates ether and toluensulfonate ether, at room temperature or under heating, preferably at room temperature in the presence of a base such as potassium carbonate, sodium hydroxide and sodium hydride, in a solvent such as diethyl ether, toluene, cyclohexane, acetone, dimethylformamide, dioxane, ethyl acetate and dimethyl sulfoxide, or a mixture of such solvents. In an alternative embodiment, the connection of the SS can be obtained by the interaction of the compounds CENTURIES with M substituted hydroxyl group, the reaction conditions of Mitsunobu.

Stage 3-3

Connection DD can be obtained by removing the protective group R"" amino compounds of the SS. Reaction conditions at this time is appropriately selected depending on the type of protecting group P"".

A common way to obtain 4

In the above formulas, R"' represents a protective group of carboxyl group; R"" represents a protective group of amino group; T represents a leaving group such as a sulphonate ester, and U represents an aryl group which may be substituted, or heteroaryl group, which may be the replacement of the military.

Stage 4-1

The connection can be obtained by the interaction of the compounds EXPLOSIVES acid chloride methanesulfonic acid, acid chloride toluensulfonate acid or anhydride triftormetilfullerenov acid at room temperature or under cooling, preferably with cooling, in the presence of a base, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-N,N-dimethylaminopyridine, in a solvent such as diethyl ether, toluene, cyclohexane, acetone, dimethylformamide, dioxane, ethyl acetate and dimethyl sulfoxide, or a mixture of such solvents.

Stage 4-2

Connection FF can be obtained by the interaction of ITS connection with a derivative of an aryl - or heteroarylboronic acid or derivative of an aryl ether - or heteroarylboronic acid at room temperature or under heating, preferably under heating in the presence of a palladium catalyst, such as paradigmatical and tetranitropentaerithrite, in a solvent such as diethyl ether, toluene, benzene, dimethylformamide, dioxane, ethyl acetate, acetonitrile and water or a mixture of such solvents.

Stage 4-3

Connection GG can be obtained by removing the protective group R" of an amino group of compound FF. Reaction conditions at this time is appropriately selected depending on the type of protective group is s P"'.

A common way to obtain 5

In the above formula R"' represents a protective group of carboxyl group; R"" represents a protective group of amino group, and U represents aryl which may be substituted, or a heteroaryl group which may be substituted.

Stage 5-1

Connection low voltage can be obtained by the interaction of the compounds CENTURIES derived from the aryl or heteroarylboronic acid derived ester aryl - or heteroarylboronic acid or halogenated aryl or halogenated heteroarylboronic at room temperature or under heating, preferably under heating in the presence of a base such as sodium hydride and potassium carbonate, or bases, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-N,N-dimethylaminopyridine, and a catalyst, such as the diacetate of copper (II) and copper iodide (I), in a solvent such as diethyl ether, toluene, cyclohexane, acetone, dimethylformamide, dioxane, methylene chloride, chloroform and dimethyl sulfoxide, or a mixture of such solvents.

Stage 5-2

Compound II can be obtained by removing the protective group R" of an amino group of compound NN. Reaction conditions at this time is appropriately selected depending on the type of the protective group R"".

In addition, this is th invention also relates to intermediate compounds for the synthesis of compounds of formula (I), which are represented by the formula:

(where R and R' may be the same or different and each represents hydroxyamino group) and the formula:

(where a, D, X and Y have the same meanings as specified).

These compounds can be obtained according to the General method of obtaining 1, which describes a method for obtaining compounds of the above formula (I).

The compound of the present invention can be applied as a medicinal product, either as such or in the form of its pharmacologically acceptable salts. There are no specific restrictions on the use of salt as it is pharmacologically acceptable, examples of salts include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and Hydrobromic acid; salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, naphthalenesulfonate acid and camphorsulfonic acid, and salts of alkali metals or alkaline-earth metals such as sodium, potassium and calcium.

Although the quantity used in quality is as active ingredient compounds, contained in the above pharmaceutical composition is not subjected to any particular limitations and appropriately selected from a wide range, it is, for example, of 0.1 to 99.5 wt.%, preferably, 0.5 to 90 wt.%.

The compound of the present invention can be manufactured using known auxiliary agent such as a filler, binder, disintegrity agent, a lubricating substance, corrigent, agent, contributing to the dissolution suspendisse agent and the agent for the formation of the coating, which is usually used in the field of technology for drugs drugs. When the drug is produced in the form of tablets, you can apply a wide range of carriers known in this field, examples of carriers include fillers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline glucose and silicic acid; binders such as water, ethanol, propanol, regular syrup, liquid glucose, liquid starch, liquid gelatin, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; dezintegriruetsja agents, such as dry starch, sodium alginate, powdered agar, powdered kelp, sodium bicarbonate, calcium carbonate, ether, polyoxy transorbital and fatty acids, sodium lauryl sulfate, monoglyceride, starch and lactose; disintegration inhibitors such as sucrose, stearin, cacao butter and hydrogenated oil; absorption promoters such as Quaternary ammonium salts and sodium lauryl sulfate; moisture retaining agents such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearate salts, powdered boric acid and polyethylene glycol.

In addition, tablets may be in the form of tablets, provided, if necessary, ordinary coating, examples of them include covered sugar tablets, encapsulated in gelatin tablets, tablets with intersolubility coating, film-coated tablets, or double-layer and multilayer tablets tablets. When molded in the form of pills as a carrier can apply to a wide range of materials, which are usually well-known in this field, examples include excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin and talc; binders such as powdered Arabian gum, powder tragakant, gelatin and ethanol; and dezintegriruetsja agents, such as agar kelp. When molded in the form of a suppository can when Enate as a carrier of a wide range of materials, which are usually known in this field, examples include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides. In case of receipt in the form of drugs for injection solution and the suspension is preferably sterilized and make them isotonic with blood and when they are made in the form of solutions, emulsions or suspensions, it is possible to use all materials which are usually used as diluents in this field, and examples include water, ethanol, propylene glycol, atoxisklerol alcohol, polycyanoacrylates alcohol and esters of polyoxyethylenesorbitan and fatty acids. In addition, in this case, the pharmaceutical preparation may contain an adequate amount of salt, glucose or glycerin to produce isotonic, you can also use the usual means of promoting dissolution, buffers, analgesic remedies, and so forth. In addition, if necessary, may also contain dyes, preservatives, flavouring means, corrigentov, sweeteners and other pharmaceuticals.

The mentioned pharmaceutical composition is preferably administered in a standard dosage form, by oral administration, injection into the skin (subcutaneous injection, vnutrimyshechnogo, intravenous and so on), local administration (percutaneous introduction and so on) or rectal administration. The above pharmaceutical composition is typically administered in a dosage form that is suitable for these techniques.

In the case of the introduction of the compounds of the present invention or its pharmaceutically acceptable salt in the form of medicines, the dose for an adult in the application as antiviral medicines, which although preferably adjusted in accordance with factors related to the patient's condition, such as age and body weight, route of administration, nature and severity of the disease and so on, is typically in the range of 0.1-2000 mg per day as the amount of the active ingredient of the present invention. Although there are cases in which the dose is less than the above range, there may be adequate, there are also cases in which, in contrast, the dose is higher than the above range may be necessary. When large doses, it is preferable to split the dose into several injections a day.

The above oral introduction can be dosed in units of solid, powdery or liquid preparation, it can be administered in the form of powder, granules, tablets, coated sugar preparations, CBSA is l, drops, sublingual drugs and other medicines.

The above introduction to tissue can be carried out using standard liquid dosage forms for subcutaneous, intramuscular or intravenous injection of a solution or suspension, and so forth. It is produced by suspendirovanie or dissolution of a certain number of compounds of the present invention or its pharmaceutically acceptable salt in a non-toxic liquid carrier that is compatible with the purpose of injection, such as water or an oil medium, followed by sterilization of the above suspension or solution.

The above local introduction (percutaneous introduction and so on) can be performed with the use of forms of the drug for external use, such as a solution, cream, powder, paste, gel or ointment. They can be obtained by mixing a certain amount of the compounds of the present invention or its pharmaceutically acceptable salt with one or more types of aromatic funds, dye, filler, surfactant, agent for moisture retention, skin softener, a gelling agent, carrier, preservative, or stabilizer, and so forth, that is appropriate for a drug for external use.

The above rectal administration can be accomplished with applications to the drug suppository and so forth, containing a certain number of compounds of the present invention or its pharmaceutically acceptable salt in a solid with a low melting point, comprising, for example, of the top of ester, such as palmately, ministerului ether, polyethylene glycol, cocoa butter or a mixture.

The above introduction may be carried out using standard liquid dosage forms for subcutaneous, intramuscular or intravenous injection, such as a solution or suspension, and so forth. They are suspendirovanie or dissolution of a certain number of compounds of the present invention or its pharmaceutically acceptable non-toxic liquid carrier suitable for injection, such as water or an oil medium, followed by sterilization of the above suspension or solution.

Example

The method of obtaining the compounds of formula (I) of the present invention and pharmacological activity of the compounds of formula (I) below is illustrated by examples.

Example 1

1-1 (stage 1-1)

Connection 1 (70.1 g), described in the above General method of obtaining 1, synthesized by the method described in literature (J. Org. Chem. 1989, 45, 5522, B.E. Marron, et al.), the solution specified connection 1 in anhydrous diethyl ether (700 m is) is cooled to 0° With and to it is slowly added bis-(2-methoxyethoxy)aluminiumtrihydrate (414 mmol, 121 ml, 70% solution in toluene). The ice bath is removed after 5 minutes after adding reagent and stirring is continued at room temperature for 1 hour. The reaction solution is cooled to 0°and to it is slowly added anhydrous ethyl acetate (19,8 ml, 203 mmol). After stirring the mixture at the same temperature for 10 minutes it was cooled to -78°C, there was added iodine (76,1 g, 300 mmol). The temperature of the mixture gradually increased to room temperature over 2 hours to complete the reaction. To the reaction solution was added water Hydrosulphite solution of the sodium and then add ethyl acetate. After filtration of the reaction solution through celite with suction organic layer is separated and the aqueous layer was once again extracted with ethyl acetate. After drying the combined organic layer over anhydrous sodium sulfate it concentrated under reduced pressure to obtain specified in the title compound (100 g) without further purification in the form of a light brown oil. The thus obtained crude product is used as such for the next reaction.

Physico-chemical properties of compounds 2

Molecular weight: 466.

FAB-MS (method of positive ions, the matrix m-NBA) 467 (M+H+).

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: 1,04 (N, C)of 1.44 (1H, t, J = 5 Hz), 2,73 (2H, t, J = 6 Hz), 3,80 (2H, t, J = 6 Hz), 4,18 (2H, t, J = 5 Hz), 5,91 (1H, t, J = 5 Hz), 7,35-7,46 (6N, m), 7,65-of 7.69 (4H, m).

1-2 (stage 1-2)

A solution of compound 2 obtained in the above reaction in dichloromethane (300 ml) cooled to 0°and to it add dihydropyran (22.7 ml, 248 mmol). To the solution was added p-toluensulfonate pyridinium (260 mg, 1 mmol). After 1 hour, to stop the reaction to it add an aqueous solution of sodium bicarbonate. The separated organic layer was washed with saturated salt solution and then it is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thus obtained compound 3 (108 g) without further purification used as such for the next reaction.

Physico-chemical properties of compounds 3

Molecular weight: 550.

FAB-MS (method of positive ions, the matrix m-NBA) 551 (M+H+).

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: was 1.04 (9H, s), 1,49 is 1.91 (6H, m), is 2.74 (2H, t, J=6 Hz), 3.46 in-to 3.58 (2H, m), 3,76 (2H, t, J=6 Hz), 3,82-3,93 (1H, m)4,06 (1H, DD, J=13, 6 Hz), 4,27 (1H, DD, J=13, 6 Hz)and 4.65 (1H, t, J=3 Hz), 5,91 (1H, t, J=5 Hz), 7,35-the 7.43 (6H, m), 7,65-of 7.69 (4H, m).

1-3 (stage 1-3)

Connection 3 (4,73 g) without further purification was dissolved in anhydrous who diethyl ether (30 ml) and the solution cooled to -78° C. To it is added slowly tert-utility (17,2 mmol, 10,7 ml of 1.6 n solution in pentane). After stirring the mixture at the same temperature for 1 hour there was added para-formaldehyde (18,9 mmol, 570 mg). The mixture was stirred at the same temperature for 30 minutes and the temperature of the mixture was raised to 0°C, followed by stirring the mixture for 1 hour. To it was added an aqueous solution of ammonium chloride to stop the reaction and the reaction mixture is extracted with ethyl acetate. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure, purified column chromatography (silica gel, hexane-ethyl acetate, 9:1-4:1), thus obtaining the compound 4 (1,635 g) as a colourless oil.

Physico-chemical properties of compounds 4

Molecular weight: 454.

FAB-MS (method of positive ions, the matrix m-NBA) 455 (M+H+).

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: was 1.04 (9H, s), 1,49-1,89 (6H, m)to 2.41 (2H, t, J=6 Hz), 3,03 (1H, t, J=6 Hz), 3,47-to 3.58 (2H, m), 3.75 to to 3.92 (3H, m), 4,08-4.26 deaths (4H, m), and 4.68 (1H, t, J=3 Hz), of 5.53 (1H, t, J=7 Hz), 7,35-7,47 (6H, m), of 7.64-to 7.68 (4H, m).

1-4 (stage 1-4)

A solution of compound 4 (344 mg, from 0.76 mmol) and imidazole (77 mg, 1,14 mmol who) in anhydrous N,N-dimethylformamide (2 ml) cooled to 0° With and to it add tert-butyldiphenylchlorosilane (0.2 ml, from 0.76 mmol) followed by stirring the mixture for 2 hours. To this mixture an aqueous solution of ammonium chloride to stop the reaction and the reaction mixture is extracted with hexane. The organic layer is washed twice with water, then with saturated salt solution and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure, thus obtaining the compound 5 (554 mg) without further purification in the form of a colorless oil.

Physico-chemical properties of compounds 5

Molecular weight: 692.

FAB-MS (method of positive ions, the matrix m-NBA) 715 (M+Na+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.00 (9H, s), was 1.04 (9H, s), 1,38-to 1.82 (6H, m), 2.49 USD (2H, t, J=7 Hz), 3,29-of 3.42 (1H, m), 3,63-of 3.85 (4H, m), EUR 4.00-4.09 to (1H, m), 4,14 (2H, s), to 4.46 (1H, t, J=3 Hz), 5,43 (1H, t, J=7 Hz), 7,29-of 7.48 (12H, m), EUR 7.57 for 7.78 (8H, m).

1-5 (stage 1-5)

p-Toluensulfonate pyridinium (90 mg, 0.36 mmol) are added to a solution of compound 5 (1,16 g, 1,67 mmol) in ethanol (6 ml) and the mixture was stirred at 60°C for 3.5 hours. After cooling the solution to room temperature, add saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution and dried over anhydrous sulfate is m sodium followed by concentration under reduced pressure. Thus obtained crude product is purified column chromatography (silica gel, hexane-ethyl acetate, 20:1), thus obtaining the compound 6 (825 mg, 81%) as a colourless oil.

Physicochemical properties of compound 6

Molecular weight: 608.

FAB-MS (method of positive ions, the matrix m-NBA) 631 (M+Na+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: a 1.01 (9H, s)a 1.01 (9H, s)of 1.23 (1H, t, J=6 Hz), is 2.41 (2H, t, J=7 Hz), of 3.75 (2H, t, J=7 Hz), 3,90 (2H, t, J=6 Hz), 4,14 (2H, s), vs. 5.47 (1H, t, J=7 Hz), 7,29-7,47 (12H, m), EUR 7.57 to 7.75 (8H, m).

1-6 (stage 1-6)

After heating round bottom flask with stir bar and drying under reduced pressure it is filled with nitrogen and add anhydrous dichloromethane (60 ml) and then cooled to -20°C. In the flask was sequentially added tetraisopropoxide titanium (2,33 ml, 7,88 mmol) and L-(+)-diethyltartrate (of 1.62 ml, 9,46 mmol) and after stirring the mixture for 15 minutes there was added a solution of compound 6 (4,80 g, 7,88 mmol) in dichloromethane (30 ml), followed by stirring the mixture for 15 minutes. The reaction mixture was cooled to -25°and to it is slowly added dropwise tert-butylhydroperoxide (the 5.25 ml, 15.8 mmol, 3 N. solution in dichloromethane). After completion of adding dropwise, the mixture is stirred at -20°within 2 hours and to it was added dimethyl sulfide (1.1 ml) with posledeistviem mixture at the same temperature for additional 1 hour. After adding to the reaction solution 10% solution of tartaric acid and stirring the mixture for 30 minutes, the mixture was stirred at room temperature for 1 hour. The organic layer is separated, the aqueous layer was extracted with a small amount of dichloromethane and the combined organic layer is dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure, purified column chromatography (silica gel, hexane-ethyl acetate, 9:1). Compound 7 (4,78 g, 97%) was obtained as a colorless oil. Asymmetric output (>95% EE (enantiomeric excess)determine the NMR analysis of the corresponding complex ester MTRA.

Physicochemical properties of compound 7

Molecular weight: 624.

FAB-MS (method of positive ions, the matrix m-NBA) 647 (M+Na+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.02 (9H, s)of 1.03 (9H, s), 1,72 (1H, t, J=6 Hz), equal to 1.82 (1H, dt, J=14, 7 Hz), of 2.23 (1H, dt, J=14, 6 Hz), 3,17 (1H, DD, J=6, 5 Hz), 3,55-with 3.79 (6H, m), 7,32 was 7.45 (12H, m), 7,60-the 7.65 (8H, m).

1-7 (stage 1 to 7)

The hydrochloride of bis-cyclopentadienylzirconium (10,11 g that 37.2 mmol) are added to a solution of compound 114 (10,45 g that 37.2 mmol)obtained in stage 2-3 the following example of getting 1, in anhydrous tetrahydrofuran (100 ml) at room temperature under nitrogen atmosphere and the mixture is stirred during the s 30 minutes. Thus obtained solution is cooled to -78°and to it add methylaniline (24,7 ml, 74 mmol, 3 N. solution in tetrahydrofuran), followed by stirring the mixture for 5 minutes. To this solution was added copper iodide (I) (500 mg, 7.2 mmol) and the temperature of the mixture gradually increased to -30°C. To it is added dropwise over 20 minutes a solution of compound 7 (of 4.49 g) in anhydrous tetrahydrofuran (70 ml) and after complete addition the mixture was stirred at -25°With during the night. To stop the reaction mixture to slowly add saturated aqueous solution of ammonium chloride and the temperature of the mixture gradually increased to room temperature. The mixture is stirred at room temperature for 10 hours and the resulting white solid is removed by filtration through celite. Celite sufficiently washed with ethyl acetate and the organic layer separated. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated aqueous ammonium chloride followed by drying over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure, purified column chromatography (silica gel, hexane-ethyl acetate, 20:1-9:1), thus obtaining the compound 8 (5,96 g, 91%) as a pale yellow oil.

Physicochemical its the STV connection 8

Molecular weight: 907.

FAB-MS (method of negative ions, the matrix m-NBA) 906 (M-N+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=7 Hz), 0,99 (9H, s), was 1.04 (9H, s), 1.18 to 1,63 (22H, m), 1,78 is 2.01 (4H, m), 2,44-to 2.57 (1H, m)of 3.00 (1H, t, J=6 Hz), 3,59-3,92 (10H, m), 4,28 (1H, s), lower than the 5.37-5,55 (2H, m), 7,29-7,65 (20H, m).

1-8 (stage 1-8)

Compound 8 (5.30 g, of 5.84 mmol) dissolved in dichloromethane (200 ml) and 2,2-dimethoxypropane (150 ml) and to the solution was added p-toluensulfonate pyridinium (15 mg, 0,058 mmol) followed by stirring the mixture at room temperature over night. To it was added a saturated aqueous sodium bicarbonate solution to stop the reaction and the reaction mixture is extracted twice with dichloromethane. The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thus obtained crude product is purified column chromatography (silica gel, hexane-ethyl acetate, 20:1). Compound 9 (4,69 g, 86%) was obtained as light yellow oil.

Physico-chemical properties of the compound (9)

Molecular weight: 947.

FAB-MS (method of negative ions, the matrix m-NBA) 946 (M-H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6 Hz), of 1.02 (9H, s)of 1.05 (9H, s), 1,14-1,63 (28H, m), 1,78-of 2.16 (4H, m), 2,41 is 2.51 (1H, m), 3,47 (1H, d, J=10 Hz), 3,64-3,86 (6H, m)to 3.92 (s, 4H), are 5.36-5,42 (2H, m), 7,28-7,47 (12H, m), 7,617,69 (8H, m).

1-9 (stage 1-9)

A solution of compound 9 (4,39 g, with 4.64 mmol) in tetrahydrofuran (50 ml) cooled to 0°and to it add tetrabutylammonium fluoride (to 10.2 ml, 10.2 mmol, 1 M solution in tetrahydrofuran) and acetic acid (0,53 ml, 9,27 mmol). The temperature of the mixture gradually increased to room temperature and the mixture is stirred for 2 days. To it was added a saturated aqueous solution of ammonium chloride and the mixture is extracted twice with dichloromethane. The combined organic layer was washed with aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. Thus obtained crude product is purified column chromatography (silica gel, hexane-ethyl acetate, 9:1-3:2), thus obtaining the compound 10 (1.73 g, 81%) as a pale yellow oil.

Physico-chemical properties of compounds 10

Molecular weight: 470.

FAB-MS (method of positive ions, the matrix m-NBA) 493 (M+Na+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6 Hz), 1,17-1,73 (26H, m), 1,91-of 2.16 (4H, m)2,44 (1H, users), by 2.73 (1H, dt, J=6, 10 Hz), 2,95 (1H, users), 3,48 (1H, d, J=11 Hz), 3,63-4,01 (m, 10H), of 5.15 (1H, DD, J=15, 9 Hz), of 5.55 (1H, dt, J=15, 7 Hz).

1-10 (stage 1-10)

The solution oxalicacid (0,575 ml, 6.6 mmol) in anhydrous dichloromethane(17 ml) is cooled to -78° In nitrogen atmosphere, and thereto is added dropwise a solution of dimethylsulfoxide (0,936 ml, 13,2 mmol) in dichloromethane (1 ml) followed by stirring the mixture for 15 minutes. To it is slowly added dropwise a solution of compound 10 (388 mg, 0,824 mmol) in dichloromethane (5 ml). After stirring the mixture at the same temperature for 1 hour and thereto added triethylamine (3 ml, with 21.4 mmol) and the mixture is additionally stirred for 30 minutes. The cooling bath is removed and after the solution blow a stream of nitrogen to remove compounds with a low boiling point, followed by drying under reduced pressure. To the residue is added diethyl ether (15 ml) and the insoluble matter is removed by filtration and the filtrate concentrated. After this procedure was conducted twice, thus obtained residue immediately used for the subsequent reaction.

The above dialdehyde without further purification was dissolved in 2-methyl-2-propanol (24 ml) and 2-methyl-2-butene (6 ml) and the mixture is cooled to approximately 5-7°C. To this solution is slowly added dropwise a solution of sodium chloride (745 mg, 8,24 mmol) and sodium dihydrophosphate (745 mg, 6.21 mmol) in water (7,45 ml). After 2 hours, the mixture is cooled to 0°and to it was added an aqueous solution of sodium dihydrophosphate for regulating the pH to approximately 5. The mixture is extracted three times with dichloromethane, and after about what ivania the combined organic layer with a saturated salt solution it is dried over anhydrous sodium sulfate. After filtration of light yellow oil is obtained by concentration under reduced pressure, immediately used for the subsequent reaction without further purification.

Dicarboxylic acid without further purification was dissolved in di-tert-butylacetate N,N-dimethylformamide (4.5 ml) and the mixture was stirred at 70°C for 1 hour. Compound with a low boiling point is distilled off under reduced pressure. The residue is purified column chromatography (silica gel, hexane-ethyl acetate, 20:1), thus obtaining the compound 11 (340 mg, 60%) as a pale yellow oil.

Physico-chemical properties of the compound (11)

Molecular weight: 610.

FAB-MS (method of positive ions, the matrix m-NBA) (M+H+) 611 (M+Na+) 633

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6 Hz), 1.18 to 1,64 (46H, m), 1,99 (2H, square, J=7 Hz), 2,69 (2H, Awkw., J=15, 18 Hz), with 2.93 (1H, square, J=7 Hz), 3,82-3,88 (2H, m)to 3.92 (4H, s), 5,51-5,69 (2H, m).

1-11 (stage 1-11)

Compound 11 (340 mg, 0,556 mmol) dissolved in tetrahydrofuran (1 ml) and to the solution was added 80% aqueous solution of acetic acid (10 ml) followed by stirring the mixture at room temperature for 3.5 hours. After slowly adding the mixture to the saturated aqueous solution of sodium bicarbonate to neutralize the acetic acid, the mixture is extracted twice with ethyl acetate. xtract dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure, thus obtaining the compound 12 (290 mg, 99%) as a pale yellow oil.

Physico-chemical properties of compounds 12

Molecular weight: 526.

FAB-MS (method of positive ions, the matrix m-NBA) (M+H+) 527 (M+Na+) 549

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=7 Hz), 1.18 to 1,68 (36H, m), a 2.01 (2H, square, J=7 Hz), 2,25-to 2.41 (5H, m), 1,99 (1H, d, J=7 Hz), 2,04 (1H, d, J=7 Hz), 3,62-3,82 (2H, m), 3,99 (1H, s), 5,42 (1H, DD, J=9, 15 Hz), to 5.58 (1H, dt, J=16, 6 Hz).

1-12 (stage 1-12)

Acetone (45 ml) cooled to 0°and to it add the reagent Jones (of 0.48 ml, 0.9 mmol, 1,89 BC). To this mixture dropwise added slowly a solution of compound 12 (216 mg, 0.41 mmol) in acetone (3 ml). After stirring the mixture at the same temperature for 1 hour and thereto to stop the reaction, add water Hydrosulphite solution of sodium to the disappearance of the yellow color of the reaction solution and the appearance of a dark green precipitate. Added a saturated salt solution (20 ml) and the mixture is extracted twice with dichloromethane. The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (dichloromethane-methanol, 50:1-20:1), thus obtaining the compound 13 (198 mg, 89%) as a pale yellow oil is).

Physico-chemical properties of compounds 13

Molecular mass: 541.

ESI (LC/MS method a positive ion (M+H+) 542

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6 Hz), 1,16-1,67 (36H, m), 1,99 (2H, square, J=6 Hz), 2,35 (4H, t, J=8 Hz), 2,70 (1H, d, J=16 Hz), 2,90 (1H, d, J=16 Hz), or 3.28 (1H, d, J=9 Hz), 5,52 (1H, DD, J=9, 15 Hz), of 5.68 (1H, dt, J=15, 5 Hz).

1-13 (stage 1-13)

A solution of compound 13 (6.0 mg, to 0.011 mmol) and hydrochloride tert-butyl ether (S)-4-phenylacetylamino (5 mg, of 0.013 mmol) in N,N-dimethylformamide (1 ml) cooled to -10°and to him successively added N,N-diisopropylethylamine (0,005 ml, 0,024 mmol) and hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (6.3 mg, 0,0166 mmol). The temperature of the mixture is slowly increased to room temperature and the mixture is stirred over night. To it was added an aqueous solution of ammonium chloride to stop the reaction and the reaction mixture is extracted with ethyl acetate. The organic layer is successively washed twice with water and then with saturated salt solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure the residue is purified by thin-layer chromatography on silica gel (hexane-ethyl acetate, 7:3), thus obtaining the compound 14 (7,6 mg, 82%) as a colourless solid.

Physico-chemical is a mini connection properties 14

Molecular weight: 835.

ESI (LC/MS, method of positive ions) 858 (M+Na+).

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6 Hz), 1,17-1,67 (45H, m)of 1.97 (2H, square, J=7 Hz), 2,33-to 2.42 (4H, m), 2,58 (1H, d, J=17 Hz), was 2.76 (1H, d, J=17 Hz), 3.00 and is 3.15 (3H, m)to 4.23 (1H, s), 4,70 (1H, square, J=8 Hz), vs. 5.47 (1H, DD, J=9, 15 Hz), the 5.65 (1H, dt, J=15, 7 Hz), 6,88-6,98 (2H, m), 7,01 for 7.12 (2H, m), 7,15-7,22 (2H, m), 7,27 was 7.36 (2H, m).

1-14 (stage 1-14)

A solution of compound 14 (7,6 mg) in dichloromethane (3 ml) cooled to 0°and to him successively added anisole (0.01 ml) and triperoxonane acid (1 ml). The temperature of the mixture is slowly increased to room temperature and the mixture is stirred over night. After concentrating the reaction solution under reduced pressure twice conduct azeotropic treatment with benzene and the residue purified using Megabond elute diol (500 mg, Barian Inc.) (dichloromethane-methanol = 20:1), thus obtaining the compound 15 (5.4 mg, 90%) as a colourless solid.

Physico-chemical properties of compounds 15

Molecular weight: 667.

ESI (LC/MS, method of positive ions) 668 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1,14-1,38 (14H, m), 1,42 is 1.58 (4H, m), 1,89 is 2.01 (2H, m), 2,37 is 2.44 (4H, m), 2,62 (1H, d, J=16 Hz), 2,88 totaling 3.04 (2H, m), 3,20-3,30 (2H, m), of 4.67 (1H, DD, J=9, 5 Hz), and 5.30-the 5.65 (2H, m), 6.87 in (2H, d, J=9 Hz)and 6.9 (2H, d, J=8 Hz), was 7.08 (1H, t, J=8 Hz), 7,20 (2H, d, J=9 Hz), 7,33 (2H, t, J=8 Hz).

Connection examples 2-97, described below, can be synthesized from corresponding compounds in a manner analogous to the method in the above example 1. Such compounds can be synthesized by a person skilled in the art from known compounds and compounds which can be easily synthesized from known compounds by a specialist in this field.

Example 2

Physico-chemical properties of compounds 16

Molecular weight: 589.

ESI (LC/MS, method of positive ions) 590 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7 Hz), 1,20-of 1.35 (14H, m), 1,46 is 1.58 (4H, m), a 1.96 (2H, square, J=5.4 Hz), and 2.27 (3H, s), 2.40 a-2,52 (5H, m), 2,84 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), of 2.92 (1H, DD, J=14, 9 Hz), 3.04 from which is 3.25 (2H, m)and 4.65 (1H, DD, J=9, 5 Hz), the 5.45 5,64 (2H, m), 7.03 is for 7.12 (4H, m).

Example 3

Physicochemical properties of compound 17

Molecular weight: 681.

ESI (LC/MS, method of positive ions) 682 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1,20-of 1.35 (14H, m), 1.41 to to 1.59 (4H, m), 1,86-of 2.20 (2H, m), 2,30-2,48 (4H, m), 2,58 (1H, d, J=16 Hz), 2,78-2,90 (2H, m), 3,11-of 3.25 (2H, m), with 4.64 (1H, DD, J=9, 4 Hz), 5,43-the ceiling of 5.60 (2H, m), 6,85-7,44 (9H, m).

Example 4

Physico-chemical properties of the compounds is of 18

Molecular weight: 643.

ESI (LC/MS, method of positive ions) 644 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7 Hz), 1,19-1,38 (14H, m), 1,42 is 1.60 (4H, m), equal to 1.82 (3H, t, J=2 Hz), 1,89-2,02 (2H, m), is 2.44 (4H, t, J=7 Hz), 2,58 (1H, d, J=16 Hz), 2,78 are 2.98 (2H, m,), 3,09 is 3.23 (2H, m), 4.53-in-4,67 (3H, m), 5,39-5,61 (2H, m), 6,83 (2H, d, J=9 Hz), 7,13 (2H, d, J=9 Hz).

The above connection 18 are synthesized using compound 18-4 in the stage 1-13 General method of obtaining 1. Connection 18-4 synthesize the following stages, proceeding from compounds 18-1.

Synthesis of compound 18-4

a) Synthesis of compound 18-2

After adding di-tert-BUTYLCARBAMATE (6,55 g, 30 mmol) to a suspension of (44 ml) of tert-butyl ester of L-tyrosine (7,12 g, 30 mmol) in absolute methanol, the mixture is stirred at room temperature for 2 hours. After concentrating the reaction solution thus obtained oil is purified column chromatography on silica gel. Compound 18-2 (9,62 g, 95%) was obtained as colorless powder processing oils obtained from part elyuirovaniya a mixture of n-hexane/ethyl acetate (2:1 → 1:1)mixture of n-hexane/ethyl acetate (10:1).

Physico-chemical properties of the compound 18-2

Molecular weight: 337.

ESI (LC/MS, method of positive ions) 338 (M+N+).

1H-NMR (deuterochloroform the magnitude of chemical shift δ : of 1.41 (9H, s)of 1.42 (9H, s), 2,90-a 3.01 (2H, m), 4,36 is 4.45 (1H, m), free 5.01 (1H, d, J=7.5 Hz), 5,67 (1H, s), 6.73 x (2H, d, J=8.5 Hz), 7,01 (2H, d, J=8,5 Hz).

b) Synthesis of compound 18-3

Potassium carbonate (173 mg, 1.25 mmol) and 1-bromo-1-butyn (147 mg, 1.1 mmol) are added to a solution (2.0 ml) of the above compound 18-2 (338 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide and the mixture is stirred at room temperature for 15 hours. To the reaction solution was added ethyl acetate (30 ml) and the solution successively washed three times with water (20 ml) and then with saturated salt solution (20 ml). The ethyl acetate layer is separated from the water and dried with anhydrous sodium sulfate and after removal of the solvent under reduced pressure, the resulting oil is purified column chromatography on silica gel. Compound 18-3 (370 mg, 95%) was obtained as colorless oil from parts elyuirovaniya a mixture of n-hexane/ethyl acetate (5:1).

Physico-chemical properties of the compound 18-3

Molecular weight: 389.

FAB-MS (method of positive ions, the matrix m-NBA) 390 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.41 (9H, s)of 1.42 (9H, s)to 1.86 (3H, t, J=2,5 Hz)of 3.00 (2H, d, J=6.0 Hz), to 4.41 (1H, DD, J=7,5, 6,0 Hz), to 4.62 (2H, square, J=2.5 Hz), equal to 4.97 (1H, d, J=7.5 Hz), to 6.88 (2H, d, J=8,5 Hz), was 7.08 (2H, d, J=8,5 Hz).

C) Synthesis of compound 18-4

Thus obtained oil (390 mg, 1.0 mmol) RA is tworay in ethyl acetate (5.0 ml) and to the solution add 4 N. hydrochloric acid in ethyl acetate (2.0 ml, 8.0 mmol) followed by stirring the mixture at room temperature for 15 hours. The precipitated powder is collected by filtration Kiriyama funnel and washed with ethyl acetate (2.0 ml) followed by drying under reduced pressure created by the vacuum pump, to obtain the compound 18-4 (278 mg, 85%) as colorless powder.

Physico-chemical properties of the compound 18-4

Molecular weight: 289.

ESI (LC/MS, method of positive ions) 290 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 1.44 (9H, s), of 1.80 (3H, t, J=2.5 Hz), 3,11 (2H, d, J=7,0 Hz), of 4.12 (1H, t, J=7.0 Hz), of 4.66 (2H, square, J=2.5 Hz), of 6.96 (2H, d, J=8.5 Hz), 7,20 (2H, d, J=8,5 Hz).

Example 5

Physico-chemical properties of compounds 19

Molecular weight: 651.

ESI (LC/MS, method of positive ions) 652 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1,10-1,57 (18H, m), 1,82-to 1.98 (2H, m), 2,32 is 2.43 (4H, m), 2.63 in (1H, d, J=16 Hz), 2,90 (1H, d, J=16 Hz), totaling 3.04 (1H, DD, J=5, 9 Hz), 3,20-of 3.25 (2H,, m), to 4.73 (1H, DD, J=9, 5 Hz), 5.40 to-5,62 (2H, m), 7,28-of 7.60 (9H, m).

Example 6

Physico-chemical properties of compounds 20

Molecular weight: 625.

ESI (LC/MS, method of positive ions) 626 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 01-1,37 (14H, m), 1,40-of 1.57 (4H, m), 1,67 and 1.80 (2H, m), 2,33 is 2.46 (4H, m)2,60 (1H, d, J=16 Hz), 2,87 (1H, d, J=16 Hz), 3,06-up 3.22 (2H, m)to 3.41 (1H, DD, J=5, 14 Hz), 4,80 (1H, DD, J=9, 4 Hz), and 5.30-of 5.48 (2H, m), 7,35-7,45 (3H, m), 7,68 (1H, s), 7,75-7,80 (3H, s).

Example 7

Physico-chemical properties of compounds 21

Molecular weight: 673.

ESI (LC/MS, method of positive ions) 674 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7 Hz), 1,19-1,62 (24H, m), 1,71-to 1.82 (2H, m), 1,89 is 2.01 (4H, m), 2,43 (4H, t, J=7 Hz), 2,61 (1H, d, J=16 Hz), 2,82-2,96 (2H, m), 3,09-of 3.27 (2H, m), 4.16 the-to 4.28 (1H, m), to 4.62 (1H, DD, J=9, 4 Hz), 5,42-the ceiling of 5.60 (2H, m), is 6.78 (2H, d, J=9 Hz), 7,10 (2H, d, J=9 Hz).

Example 8

Physico-chemical properties of compounds 22

Molecular weight: 659.

ESI (LC/MS, method of positive ions) 660 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: 0,81 to 0.92 (9H, m), 1,15-1,63 (23H, m), 1,88 is 2.01 (2H, m), 2,43 (4H, t, J=7 Hz), 2,48-2,62 (3H, m), 2,79 are 2.98 (2H, m), 3,12-of 3.27 (2H, m)and 4.65 (1H, DD, J=9.4 Hz), 5,44-5,59 (2H, m), 7,06 (2H, d, J=8 Hz), 7,12 (2H, d, J=8 Hz).

Example 9

Physico-chemical properties of compounds 23

Molecular weight: 635.

ESI (LC/MS, method of positive ions) 636 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,17-1,36 (14H, m), 1,45-to 1.60 (4H, m), 1,90-2,02 (2H, m), 2,41 at 2.45 (4H, m), 2,53 (1H, d, J=16.0 Hz), 2,87 (1H, d, J=16.0 Hz), of 2.92 (1H, DD, J=8,8, of 14.0 Hz), 3,16-3,20 (2H, m), of 3.78 (3H, what), of 3.80 (3H, s), of 4.67 (1H, DD, J=4,8, and 9.2 Hz), 5,47-to 5.58 (2H, m), of 6.75 (1H, m), 6,82-6,84 (2H, m).

Example 10

Physico-chemical properties of compounds 24

Molecular weight: 701.

ESI (LC/MS, method of positive ions) 702 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), of 1.23 to 1.31 (14H, m), 1,48-and 1.54 (4H, m), 1,95 (2H, square, J=6.9 Hz), 2,38 is 2.43 (4H, m)2,60 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), 2,96 (1H, DD, J=9,2, 14.4 Hz), 3,20 (1H, d, J=5.6 Hz), 3,21 (1H, DD, J=9,2, 14.4 Hz), of 4.67 (1H, DD, J=4,8, and 9.2 Hz), 5,47-the ceiling of 5.60 (2H, m), 6.89 in (2H, d, J=6.4 Hz), 6,91 (2H, d, J=8,8 Hz), 7,22 (2H, d, J=8,8 Hz), 7,32 (2H, d, J=6,4 Hz).

Example 11

Physico-chemical properties of compounds 25

Molecular weight: 685.

ESI (LC/MS, method of positive ions) 686 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,19-1,37 (14H, m), 1,46 is 1.58 (4H, m), 1,88 is 2.00 (2H, m), 2,39 is 2.44 (4H, m), 2,59 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), 2.95 and are 2.98 (1H, m), 3,19-3,24 (2H, m), of 4.66 (1H, DD, J=4,4, 9,2 Hz), 5,51-to 5.58 (2H, m), at 6.84-6.87 in (2H, m), 6,95-6,99 (2H, m), 7,05-7,10 (2H, m), 7.18 in-7,21 (2H, m).

Example 12

Physico-chemical properties of compounds 26

Molecular weight: 645.

ESI (LC/MS, method of positive ions) 646 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (6H, t, J=6.8 Hz), 1,20-of 1.39 (18H, m), 1,49-of 1.62 (6H, m), 1,95-to 1.98 (2H, m), 2,41 at 2.45 (4H, m)to 2.55 (2H, t, J=7.8 Hz), 2,56 (1H, d, J=16 Hz), 2,87 (H, d, J=16 Hz), 2,95 (1H, DD, J=8,8, of 14.0 Hz), 3,17-3,24 (2H, m), of 4.66 (1H, DD, J=4,4, 8,8 Hz), 5,47-5,61 (2H, m), 7,06 (2H, d, J=8,4 Hz), 7,11 (2H, d, J=8,4 Hz).

Example 13

Physico-chemical properties of compounds 27

Molecular weight: 652.

ESI (LC/MS, method of positive ions) 653 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,17-1,20 (4H, m), of 1.23 and 1.35 (10H, m), 1,45-and 1.54 (4H, m)of 1.93 (2H, square, J=6.4 Hz), 2,38 is 2.44 (4H, m), 2,47 (1H, d, J=16.0 Hz), 2,85 (1H, d, J=16.0 Hz), of 3.07 (1H, DD, J=9,4, of 14.0 Hz), 3,17 (1H, d, J=8,4 Hz), the 3.35 (1H, m), 4,78 (1H, DD, J=4,8, and 9.2 Hz), 5,52-to 5.58 (2H, m), 7,45 (2H, d, J=8,2 Hz), to 7.68 (2H, d, J=8,2 Hz), 7,89-to 7.93 (1H, m), 8,58-8,61 (1H, m), to 8.70 (1H, d, J=4.4 Hz), 9,01 (1H, d, J=1.6 Hz).

Example 14

Physico-chemical properties of compounds 28

Molecular weight: 685.

ESI (LC/MS, method of positive ions) 686 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1,17-of 1.18 (4H, m), 1,20-1,36 (10H, m), 1,46-of 1.56 (4H, m), with 1.92 (2H, square, J=6.4 Hz), 2,36 is 2.44 (4H, m), 2,61 (1H, d, J=17 Hz), 2.91 in (1H, d, J=17 Hz), totaling 3.04 (1H, DD, J=8,8, of 14.0 Hz), 3,19 (1H, d, J=8,4 Hz), 3,29 (1H, DD, J=8,8, 14 Hz), and 4.75 (1H, DD, J=9,2 Hz), 5,49-the ceiling of 5.60 (2H, m), 7,30 (2H, d, J=8.0 Hz), 7,40 (2H, d, J=8.0 Hz), to 7.50 (2H, d, J=8.0 Hz), 7,55 (2H, d, J=8.0 Hz).

Example 15

Physico-chemical properties of compounds 29

Molecular weight: 669.

ESI (LC/MS, method of positive ions) 670 (M+H+).

1H-NMR (in methanol d-4) values of the chemical shift δ : to 0.89 (3H, t, J=6.8 Hz), 1,10-1,19 (4H, m), 1,19-of 1.35 (10H, m), 1,38-and 1.54 (4H, m), at 1.91 (2H, square, J=6.5 Hz), 2,35 is 2.43 (4H, m)2,60 (1H, d, J=16,8 Hz), 2,90 (1H, d, J=16.0 Hz), to 3.02 (1H, DD, J=9,6, of 14.0 Hz), 3.27 to (1H, d, J=5,2 Hz), 3,30-to 3.33 (1H, m), to 4.73 (1H, DD, J=4,8, and 9.2 Hz), 5,49 is 5.54 (2H, m), 7,12-7,17 (2H, m), 7,30 (2H, d, J=8,4 Hz), 7,49 (2H, d, J=8,4 Hz), 7,58-to 7.61 (2H, m).

Example 16

Physico-chemical properties of compounds 30

Molecular weight: 687.

ESI (LC/MS, method of positive ions) 688 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,11-1,25 (4H, m), 1,25-1,35 (10H, m), 1,40-1,60 (4H, m)of 1.93 (2H, square, J=6,7 Hz), 2,36 is 2.43 (4H, m), 2,61 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), totaling 3.04 (1H, DD, J=9,6, of 14.0 Hz), 3,21 (1H, d, J=8.0 Hz), 3.27 to 3.30 levels (1H, m), 4,74 (1H, DD, J=4,4, 9,2 Hz), 5,47-to 5.58 (2H, m), 7,00-7,05 (2H, m), 7,31 (2H, d, J=8,4 Hz), 7,41 (2H, d, J=8,4 Hz), 7,43-7,51 (1H, m,).

Example 17

Physico-chemical properties of compounds 31

Molecular weight: 657.

ESI (LC/MS, method of positive ions) 658 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,17-1,19 (4H, m), of 1.20 to 1.34 (10H, m), 1,45-1,55 (4H, m), at 1.91 (2H, square, J=6.4 Hz), 2,36 is 2.44 (4H, m), 2.63 in (1H, d, J=16,8 Hz), 2.91 in (1H, d, J=16.0 Hz), to 3.00 (1H, DD, J=9,2, 14.4 Hz), 3,20 (1H, d, J=8.0 Hz), 3,26 (1H, DD, J=9,2, 14.4 Hz), to 4.73 (1H, DD, J=4,8, and 9.2 Hz), 5,46-of 5.53 (2H, m), 7,25 (2H, d, J=8,4 Hz), 7,39 was 7.45 (2H, m), 7,53-of 7.55 (3H, m).

Example 18

Physicochemical properties of compound 32 (mixture of diastereomers)

MOLEKULYaRNAYa weight: 643.

ESI (LC/MS, method of positive ions) 644 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,19-1,38 (14N, m), 1,46-to 1.59 (4H, m), 1,90-2,00 (2H, m), 2,38-2,47 (4H, m), 2,54 at 2.59 (1H, m), 2,75-only 2.91 (1H, m), 3.04 from-3,19 (2H, m), 3,31-3,37 (1H, m,), 4,72 was 4.76 (1H, m), 5,43-the ceiling of 5.60 (2H, m), 7,41-7,44 (2H, m), 7,54-to 7.59 (2H, m).

Example 19

Physico-chemical properties of compounds 33

Molecular weight: 600.

ESI (LC/MS, method of positive ions) 601 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1,19-of 1.35 (14H, m), 1,48 is 1.58 (4H, m), 1,90-2,00 (2H, m), 2,42 at 2.45 (4H, m), of 2.51 (1H, d, J=16 Hz), 2,87 (1H, d, J=16 Hz), 3,06 (1H, DD, J=9,6, 14 Hz), 3,14 (1H, d, J=4.4 Hz), 3.33 and-3,37 (1H, m), and 4.75 (1H, DD, J=4,8, and 9.6 Hz), 5,44-to 5.57 (2H, m), 7,42 (2H, d, J=8.0 Hz), 7,63 (2H, d, J=8.0 Hz).

Example 20

Physico-chemical properties of compounds 34

Molecular weight: 609.

ESI (LC/MS, method of positive ions) 610 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: 0,91-and 0.98 (3H, m), 1,17-of 1.40 (14H, m), 1.41 to of 1.62 (4H, m), 1.85 to 2,03 (2H, m), a 2.36-2,48 (4H, m), of 2.51-2,62 (1H, m), 2,82-to 3.02 (2H, m), 3,12 of 3.28 (2H, m), br4.61-4,71 (1H, m), 5.40 to-5,62 (2H, m), 7,12-7,30 (4H, m).

Example 21

Physicochemical properties of compound 35 (mixture of diastereomers)

Molecular weight: 620.

ESI (LC/MS, method of positive ions) 621 (M+H+)

1H-NMR (in methanol d-4) Velich the chemical shift δ : to 0.89 (3H, t, J=7.0 Hz), 1,17-of 1.35 (14H, m), 1,44 is 1.58 (4H, m), 1,89 of 1.99 (2H, m), a 2.36-2.49 USD (5H, m), 2,68-is 2.88 (1H, m), is 3.08-and 3.16 (2H, m), 3,38-3,44 (1H, m), 4,77 of 4.83 (1H, m), 5,46-to 5.58 (2H, m), 7,46-7,51 (2H, m), 8,12-8,18 (2H, m).

Example 22

Physico-chemical properties of compounds 36

Molecular weight: 581.

ESI (LC/MS, method of positive ions) 582 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,25-1,43 (14H, m), 1,50-and 1.54 (4H, m), from 2.00 (2H, square, J=6.4 Hz), 2,41 at 2.45 (4H, m), 2,65 (1H, d, J=16.0 Hz), 2,86 (1H, d, J=16.0 Hz), 3,21 (1H, d, J=and 17.2 Hz), with 3.27 (1H, DD, J=5,2, 14,8 Hz), 3,42 (1H, DD, J=5,2, 14,8 Hz), of 4.67 (1H, DD, J=5,2, 8.0 Hz), of 5.53-to 5.66 (2H, m), 6,88-of 6.90 (2H, m), 7,19-7,21 (1H, m).

Example 23

Physico-chemical properties of compounds 37

Molecular weight: 631.

ESI (LC/MS, method of positive ions) 632 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: 0,89 (ZN, t, J=7.0 Hz), 1,21-1,39 (23H, m), 1,48 is 1.58 (4H, m)of 1.97 (2H, square, J=6.4 Hz), 2,41 at 2.45 (4H, m), 2,59 (1H, d, J=16.4 Hz), 2,88 (1H, d, J=16.4 Hz), 2,96 (1H, DD, J=8,8, 14.4 Hz), 3,16-is 3.21 (2H, m)and 4.65 (1H, DD, J=4,4, 8,8 Hz), 5,49-5,64 (2H, m), 7,14 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz).

Example 24

Physicochemical properties of compound 38

Molecular weight: 685.

ESI (LC/MS, method of positive ions) 686 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,07-1,19 (4H, m), 1,19 is 1.34 (10H, m), 1,45-1,55 (4H, m), 190 (2H, square, J=6.4 Hz), 2,33 is 2.43 (4H, m), 2,61 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), to 3.02 (1H, DD, J=10,0, of 14.0 Hz), 3,19 (1H, d, J=8.0 Hz), 3.27 to and 3.31 (1H, m), 4,72-of 4.77 (1H, m), 5,44-of 5.55 (2H, m), 7,32 (3H, m), 7,40 (1H, m), 7,52 (3H, m), 7,58 (1H, s)

Example 25

Physico-chemical properties of compounds 39

Molecular weight: 701.

ESI (LC/MS, method of positive ions) 702 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,15-1,37 (14H, m), 1.41 to was 1.58 (4H, m), 1,90-2,00 (2H, m), is 2.41 (4H, square, J=7,2 Hz), 2,61 (1H, d, J=16.0 Hz), 2,92 (1H, d, J=16.4 Hz), 2,98 (1H, DD, J=9,6, of 14.0 Hz), 3,21 (1H, d, J=8,8 Hz), with 3.27 (1H, DD, J=9,6, of 14.0 Hz), 4,69 (1H, DD, J=5,2, 9.6 Hz), 5,46-5,63 (2H, m), 6,85-to 6.88 (1H, m), 6,91-6,93 (3H, m), 7,06-to 7.09 (1H, m), 7,25 (2H, d, J=8,8 Hz), 7,30 (1H, m,).

Example 26

Physico-chemical properties of compounds 40

Molecular weight: 647.

ESI (LC/MS, method of positive ions) 648 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ:to 0.80 (3H, t, J=7 Hz), and 0.98 (3H, t, J=7 Hz), 1,19-1,62 (20H, m), 1.91 a-2,03 (2H, m), 2,38 is 2.46 (4H, m), 2.57 m (1H, d, J=8 Hz), 2,84-2,96 (2H, m), 3,11-of 3.23 (2H, m), 3,92 (2H, t, J=7 Hz), 4,63 (1H, DD, J=9, 5 Hz), 5,42-5,61 (2H, m), to 6.80 (2H, d, J=9 Hz), 7,11 (2H, d, J=9 Hz).

Example 27

Physico-chemical properties of compounds 41

Molecular weight: 633.

ESI (LC/MS, method of positive ions) 634 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7 Hz), of 1.03 (3H, t, =7 Hz), 1,17-of 1.40 (14H, m), 1,43 is 1.60 (4H, m), 1.77 in (2H, square, J=7 Hz), 1,91 is 2.01 (2H, m), 2,39-2,49 (4H, m), of 2.56 (1H, d, J=17 Hz), 2,80-of 2.97 (2H, m), of 3.10-3.20 (2H, m), 3,88 (2H, t, J=7 Hz), with 4.64 (1H, DD, J=9, 5 Hz), 5,42-5,61 (2H, m), to 6.80 (2H, d, J=9 Hz), 7,12 (2H, d, J=9 Hz).

Example 28

Physico-chemical properties of compounds 42

Molecular weight: 631.

ESI (LC/MS, method of positive ions) 632 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1,14-1,38 (14H, m), 1,42 is 1.58 (4H, m), 1,89 is 2.01 (2H, m), 2,37 is 2.46 (4H, m), 2.57 m (1H, d, J=16 Hz), 2,82-2,96 (2H, m), 3,11-up 3.22 (2H, m), 4,45-to 4.52 (2H, m), 4,63 (1H, DD, J=9, 4 Hz), with 5.22 (1H, DD, J=10.1 Hz), lower than the 5.37, (1H, DD, J=17,1 Hz), the 5.45 5,59 (2H, m), 5,97-6,10 (1H, m), PC 6.82 (2H, d, J=9 Hz), 7,14 (2H, d, J=9 Hz).

Example 29

Physico-chemical properties of compounds 43

Molecular weight: 605.

ESI (LC/MS, method of positive ions) 606 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7 Hz), 1.18 to of 1.40 (14H, m), 1,42 is 1.58 (4H, m), 1,91 is 2.01 (2H, m), 2,38-2,47 (4H, m), 2,53 (1H, d, J=15 Hz), 2,80-of 2.97 (2H, m), 3,11-is 3.21 (2H, m in), 3.75 (3H, C), with 4.64 (1H, DD, J=9, 5 Hz), 5,44-5,62 (2H, m), for 6.81 (2H, d, J=9 Hz), 7,13 (2H, d, J=9 Hz).

Connection 44-52 can be synthesized from compound 8 in a manner analogous to the method of connection 15.

Example 30

Physico-chemical properties of compounds 44

Molecular weight: 661.

FAB-MS (method of positive ions, the matrix m-NBA) 662 (M+H+

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7 Hz), is 0.96 (6H, d, J=6.5 Hz), 1,19-1,37 (14H, m), 1,46 is 1.58 (4H, m)of 1.64 (2H, square, J=6.5 Hz), 1,74-1,89 (1H, m), 1,92 is 2.00 (2H, m), 2,43 (4H, t, J=7.5 Hz,), 2,59 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), of 2.92 (1H, DD, J=14, 9 Hz), and 3.16 (1H, DD, J=14 and 4.5 Hz), 3,21 (1H, d, J=8 Hz), of 3.95 (2H, t, J=6.5 Hz), 4,63 (1H, DD, J=9 and 4.5 Hz), 5,44-5,61 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 31

Physico-chemical properties of compounds 45

Molecular weight: 661.

FAB-MS (method of positive ions, the matrix m-NBA) 662 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), is 0.96 (6H, d, J=6.5 Hz), 1,20-of 1.35 (14H, m), 1,45-of 1.57 (4H, m)of 1.64 (2H, square, J=6.5 Hz), 1,74-1,89 (1H, m), 1,94 is 2.01 (2H, m), 2,39 at 2.45 (4H, m), 2,59 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), 2,90 (1H, DD, J=14, 9 Hz), and 3.16 (1H, DD, J=14 and 4.5 Hz), 3,20 (1H, d, J=8.5 Hz), of 3.96 (2H, t, J=6.5 Hz), with 4.64 (1H, DD, J=9 and 4.5 Hz), 5,46-the ceiling of 5.60 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 32

Physico-chemical properties of compounds 46

Molecular weight: 605.

FAB-MS (method of positive ions, the matrix m-NBA) 606 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7.5 Hz), is 0.96 (6H, d, J=6.5 Hz), of 1.20 and 1.35 (6H, m), 1,47 is 1.58 (4H, m), of 1.65 (2H, square, J=6.5 Hz), 1,74-1,89 (1H, m), 1.93 and is 2.00 (2H, m), 2,42 (4H, t, J=7.5 Hz,), 2,59 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), 2,90 (1H, DD, J=14, 9 Hz), and 3.16 (1H, DD, J=14 and 4.5 Hz), 3,20 (1H, d, J=8.5 Hz), of 3.95 (2H, t, J=6.5 Hz), with 4.64 (1H, DD, J=9 and 4.5 Hz), the 5.45 5,61 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 33

Physico-chemical properties of compounds 47

Molecular weight: 667.

FAB-MS (method of positive ions, the matrix m-NBA) 668 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δas 0.96 (6H, d, J=6.5 Hz), 1.18 to about 1.36 (6H, m), 1,44-and 1.54 (2H, m), and 1.63 (2H, square, J=6.5 Hz), 1,73-of 1.88 (1H, m), 1,90-to 1.98 (2H, m), 2,39 (2H, t, J=7.5 Hz), 2,59 (1H, d, J=16 Hz), 2,72-2,95 (6H, m)and 3.15 (1H, DD, J=14 and 4.5 Hz), 3,20 (1H, d, J=7.5 Hz), of 3.94 (2H, t, J=6.5 Hz), 4,63 (1H, DD, J=9 and 4.5 Hz), 5,44-the ceiling of 5.60 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,10 (2H, d, J=8.5 Hz), 7,14-7,27 (5H, m).

Example 34

Physico-chemical properties of compounds 48

Molecular weight: 659.

FAB-MS (method of positive ions, the matrix m-NBA) 660 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: 0,96 (6N, d, J=6.5 Hz), 1,21-1,42 (10H, m), 1,48-of 1.57 (4H, m)of 1.64 (2H, square, J=6.5 Hz), 1,76 is 1.91 (1H, m), 1.93 and-of 2.08 (4H, m), 2.40 a is 2.46 (4H, m), 2,59 (1H, d, J=16 Hz), 2,88 (1H, d, J=16 Hz), 2,90 (1H, DD, J=14, 9 Hz), and 3.16 (1H, DD, J=14, 5 Hz), 3,21 (1H, d, J=7.5 Hz), of 3.95 (2H, t, J=6.5 Hz), 4,63 (1H, DD, J=9, 5 Hz), 4,78-5,02 (2H, m), the 5.45 ceiling of 5.60 (2H, m), 5,80 (1H, DDT,, J=17, 10, 7 Hz), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz)

Example 35

Physico-chemical properties of compounds 49

Molecular weight: 675.

ESI (LC/MS, method of positive ions) 676 (M+N+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 0,96 (6N, d, J=6.5 Hz), 1,17-140 (N, m), 1,42 is 1.58 (4H, m)of 1.64 (2H, square, J=6.5 Hz), 1,73-of 1.88 (1H, m), 1,89-2,03 (2H, m), 2,43 (4H, t, J=7.5 Hz), 2,58 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), 2,92 (1H, d, J=14 Hz), is 3.08-3.24 in (2H, m), 3.95 to (2H, t, J=6.5 Hz), with 4.64 (1H, DD, J=8, and 5.5 Hz), 5,47-to 5.58 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 36

Physico-chemical properties of compounds 50

Molecular weight: 661.

ESI (LC/MS, method of positive ions) 662 (M+N+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: 0,87 (6N, d, J=6.5 Hz), 0,96 (6N, d, J=6.5 Hz), 1,08-1,42 (10H, m), 1,42 is 1.58 (5H, m)of 1.64 (2H, square, J=6.5 Hz), 1,72-to 1.87 (1H, m), 1,89-2,04 (2H, m), 2,43 (4H, m), 2,58 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), 2,92 (1H, d, J=14 Hz), is 3.08 is 3.23 (2H, m), of 3.95 (2H, t, J=6.5 Hz), with 4.64 (1H, DD, J=9, 5 Hz), 5,46-to 5.58 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 37

Physico-chemical properties of compounds 51

Molecular weight: 647.

FAB-MS (method of positive ions, the matrix m-NBA) 648 (M+N+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), 0,96 (6N, d, J=6.5 Hz), of 1.20 to 1.37 (N, m), 1,45-of 1.57 (4H, m)of 1.64 (2H, square, J=6.5 Hz), 1,74-1,89 (1H, m), 1.93 and is 2.00 (2H, m), 2,43 (4H, t, J=7 Hz), 2,59 (1H, d, J=16 Hz), 2,89 (1H, d, J=16 Hz), only 2.91 (1H, DD, J=14, 9 Hz), and 3.16 (1H, DD, J=14 and 4.5 Hz), 3,20 (1H, d, J=6.5 Hz), of 3.95 (2H, t, J=6.5 Hz), 4,63 (1H, DD, J=9 and 4.5 Hz), the 5.45 ceiling of 5.60 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 38

Physico-chemical properties of compounds 52

Molecular weight of 673.

ESI (LC/MS, method of positive ions) 674 (M+N+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: 0,96 (6N, d, J=6.5 Hz), of 1.09 to 1.37 (11N, m), 1,37 is 1.58 (4H, m), 1,60-1,75 (8H, m), 1,75-1,90 (1H, m), 1.91 a-2,03 (2H, m), 2,43 (4H, m), 2.57 m (1H, d, J=16 Hz), 2,88 (1H, d, J=16 Hz), 2,85-2,95 (1H, m), 3,10-3,24 (2H, m), of 3.94 (2H, t, J=6.5 Hz), 4,63 (1H, DD, J=5, 9 Hz), 5,44-the ceiling of 5.60 (2H, m), is 6.78 (2H, d, J=8.5 Hz), 7,10 (2H, d, J=8,5 Hz).

Example 39

Physico-chemical properties of compounds 53

Molecular weight: 681.

ESI (LC/MS, method of positive ions) 682 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7 Hz), 1.18 to 1,36 (14H, m), 1,45 is 1.58 (4H, m), 1.93 and-to 1.98 (2H, m), 2,31 (3H, s), 2,38-to 2.42 (4H, m), 2,61 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), 2,95 (1H, DD, J=9,2, of 14.0 Hz), 3,18 is 3.23 (2H, m), of 4.66 (1H, DD, J=9,2, 4,4 Hz), 5,47-5,59 (2H, m), for 6.81-6,86 (4H, m), 7,13-to 7.18 (4H, m).

The above connection 53 synthesized using compounds 53-3 in stage 1-13 General method of obtaining 1 and the connection 53-3 synthesize the following stages.

The synthesis of compounds 53-3

a) Synthesis of compounds 53-1

Di-tert-BUTYLCARBAMATE (24,4 ml, 106 mmol) is slowly added dropwise to a suspension of tert-butyl ester of L-tyrosine (25 g, 105 mmol), available on the market, in methanol (150 ml). She gradually dissolved by adding dropwise the specified ether, and the thus obtained R is the target stirred for one hour. After concentrating the reaction solution to the thus obtained residue add a solution of a mixture of hexane (90 ml) and ethyl acetate (10 ml) and powdered residue obtained by treatment of the mixture with ultrasonic waves. Thus obtained powder was filtered Kiriyama funnel, while receiving 31.0 g (87.6 per cent) connection 53-1 in the form of a white powder.

Physico-chemical properties of compounds 53-1

ESI (LC/MS, method of positive ions) 338 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.41(9H,s)of 1.43(9H, s), 2,96-a 3.01 (2H, m), 4,37 was 4.42 (1H, m), 4,98-5,10 (1H, m), 5,78 (1H, s) 6,70 to 6.75 (2H, m), of 6.96-7,05 (2H, m).

b) Synthesis of compounds 53-2

To connect 53-1 (169 mg, 0.5 mmol)obtained above reaction in the solvent dichloromethane (5.0 ml) of the diacetate of copper (II) (114 mg, of 0.625 mmol), 4-methylphenylacetic acid (175 mg, 1.25 mmol) and molecular sieves 4 E (500 mg), is added dropwise pyridine (0.2 ml, 2.5 mmol) by the method described in literature (Tetrahedron Lett., 1998, 39, 2937). After 13 hours, the reaction solution is concentrated and to the thus obtained residue added ethyl acetate and the insoluble matter is filtered off on celite. Celite washed three times with ethyl acetate and the filtrate concentrated under reduced pressure. Thus obtained crude product is purified column chromatography (silicagel is, hexane-ethyl acetate, 5:1) to obtain compound 53-2 (210 mg, 98%) as a colourless oil.

Physico-chemical properties of compounds 53-2

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.41 (9H, s)of 1.43 (9H, s), of 2.33 (3H, s), 2,92-to 3.09 (2H, m), 4,36-4,48 (2H, m) 4,94-of 5.06 (2H, m), 6,83-6,94 (4H, m), 7.18 in-7,28 (4H, m)

C) Synthesis of compounds 53-3

Connection 53-2 (204 mg, 0.48 mmol)obtained as above is dissolved in anhydrous ethyl acetate (2.5 ml) and the solution slowly added dropwise at room temperature add 4 N. hydrochloric acid in ethyl acetate (0,96 ml of 3.84 mmol). After stirring the mixture at room temperature for 17 hours formed white precipitate is collected by filtration on a Kiriyama funnel and washed with ethyl acetate. Thus obtained product is dried under reduced pressure, thus obtaining the connection 53-3 (127 mg, 73%) as a white powder.

Physico-chemical properties of compounds 53-3

ESI (LC/MS, method of positive ions) 328 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.43 (9H, s), 2,32 (3H, s), 3,12-3,18 (2H, m), is 4.15 (1H, t, J=7,1 Hz), 6,84-6,89 (2H, m), 6.90 to-6,98 (2H, m), 7,14-7,19 (2H, m), 7,22-7,27 (2H, m)

Example 40

Physico-chemical properties of compounds 54

Molecular weight: 697.

ESI (LC/MS, method of positive ions) 698 (M+H+ )

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,17-1,36 (14H, m), 1,44-of 1.56 (4H, m), 1,88 of 1.99 (2H, m), 2,39 is 2.43 (4H, m)2,60 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), 2.91 in-2,96 (1H, m), 3,17-3,22 (2H, m), of 3.78 (3H, s)and 4.65 (1H, DD, J=9,0, 4.6 Hz), 5,47-5,61 (2H, m), 6,78-for 6.81 (2H, m), 6.89 in-6,93 (4H, m), 7,13-7,16 (2H, m).

Example 41

Physico-chemical properties of compounds 55

Molecular weight: 735.

ESI (LC/MS, method of positive ions) 736 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1.18 to 1,36 (14H, m), 1,43 is 1.58 (4H, m), 1,90-2,00 (2H, m), 2,38 is 2.43 (4H, m), 2,61 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), 2,99 (1H, DD, J=14,0 and 9.6 Hz), 3,21 (1H, d, J=8,8 Hz), 3,26 (1H, DD, J=14,0, 4.6 Hz), 4,70 (1H, DD, J=9,6, 4.6 Hz), 5,48-5,62 (2H, m), 6,95-6,99 (2H, m), 7,06 (2H, d, J=8,2 Hz), 7,27-7,29 (2H, m), a 7.62 (2H, d, J=8,2 Hz).

Example 42

Physico-chemical properties of compounds 56

Molecular weight: 681.

ESI (LC/MS, method of positive ions) 682 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1.18 to 1,34 (14H, m), 1,42 is 1.58 (4H, m), 1,90 of 1.99 (2H, m), is 2.30 (3H, s), 2,35 is 2.43 (4H, m), 2,62 (1H, d, J=14,0 Hz), 2.91 in (1H, d, J=14,0 Hz), 2,96 (1H, DD, J=12,8, 8.5 Hz), 3,19-3,24 (2H, m), of 4.66 (1H, DD, J=4,8, 8.5 Hz), 5,48-the ceiling of 5.60 (2H, m), 6,72-of 6.78 (1H, m), 6,74-of 6.78 (1H, m), 6,84-6,86 (2H, m), 6.90 to-6,92 (1H, m), 7.18 in-7,21 (3H, m).

Example 43

Physico-chemical properties of compounds 57

Molecular weight: 735.

ESI(LC/MS, the way of positive ions) 736 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,16-1,34 (14H, m), 1,42 is 1.58 (4H, m), 1,89 of 1.99 (2H, m), 2,34 is 2.43 (4H, m)2,60 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), 2,99 (1H, DD, J=14,0, 9,2 Hz), 3,21 (1H, d, J=8,4 Hz), 3,26 (1H, DD, J=4,8, of 14.0 Hz), 4,69 (1H, DD, J=9,2, 4,8 Hz), 5,49-the ceiling of 5.60 (2H, m), 6,93-of 6.96 (2H, m), 7,16-7,20 (2H, m), 7,26-7,28 (2H, m), of 7.36-7,38 (1H, m), 7,50-rate of 7.54 (1H, m).

Example 44

Physico-chemical properties of compounds 58

Molecular weight: 681.

ESI (LC/MS, method of positive ions) 682 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), of 1.09 to 1.34 (14H, m), 1,38-of 1.55 (4H, m), 1,84-of 1.92 (2H, m), 2,27-to 2.42 (4H, m), 2.63 in (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), of 3.00 (1H, DD, J=9,6, of 14.0 Hz), 3,20 (1H, d, J=8.0 Hz), with 3.27 (1H, DD, J=4,4, of 14.0 Hz), 3,81 (3H, s), 4.72 in (1H, DD, J=9,6, 4,4 Hz), 5,48-5,52 (2H, m), of 6.96-6,98 (2H, m), 7,26 (2H, d, J=8,2 Hz), 7,47 (2H, d, J=8,2 Hz), 7,50-7,52 (2H, m,).

Example 45

Physico-chemical properties of compounds 59

Molecular weight: 665.

ESI (LC/MS, method of positive ions) 666 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,09-1,19 (4H, m), to 1.21 and 1.35 (10H, m), 1,38 is 1.58 (4H, m), 1,86-of 1.94 (2H, m), 2,30-2,42 (7H, m), 2.63 in (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), 3,00 (1H, DD, J=9,6, of 14.0 Hz), 3,20 (1H, d, J=8,4 Hz), 3,25 of 3.28 (1H, m), 4.72 in (1H, DD, J=of 9.6, 4.8 Hz), the 5.45 of 5.53 (2H, m), 7,22 (2H, d, J=8.0 Hz), 7,27 (2H, d, J=8.0 Hz), 7,46 is 7.50 (4H, m).

Example 46

Physico-chemical properties of compounds 60

Molecular weight: 719.

ESI (LC/MS, method of positive ions) 720 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,09-1,19 (4H, m), 1,19-of 1.33 (10H, m), 1,38-of 1.57 (4H, m), 1.85 to was 1.94 (2H, m), 2,30-to 2.42 (4H, m), 2,58 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), 3.04 from (1H, DD, J=14.2 per cent and 9.6 Hz), 3,19 (1H, d, J=8,4 Hz), 3,30-to 3.34 (1H, m), and 4.75 (1H, DD, J=9,6, 4.6 Hz), 5,46-to 5.57 (2H, m), of 7.36 (2H, d, J=8,4 Hz), 7,60 (2H, d, J=8,4 Hz), 7,72 (2H, d, J=8,4 Hz), 7,79 (2H, d, J=8,4 Hz).

Example 47

Physico-chemical properties of compounds 61

Molecular weight: 665.

ESI (LC/MS, method of positive ions) 666 (M+H+).

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,09 is 1.20 (4H, m), of 1.20 to 1.34 (10H, m), 1,38-of 1.56 (4H, m), 1.85 to of 1.93 (2H, m), 2,32-2,42 (7H, m)of 2.64 (1H, d, J=16.0 Hz), 2,92 (1H, d, J=16.0 Hz), 3,01 (1H, DD, J=9,6, of 14.0 Hz), 3,21 (1H, d, J=8.0 Hz), 3,26-3,30 (1H, m), to 4.73 (1H, DD, J=9,6, 4.6 Hz), the 5.45 of 5.53 (2H, m), 7,12 - 7,14 (1H, m), 7,26-7,30 (3H, m), 7,35-7,40 (2H, m), 7,49 - 7,51 (2H, m).

Example 48

Physico-chemical properties of compounds 62

Molecular weight: 681.

ESI (LC/MS, method of positive ions) 682 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,08 is 1.20 (4H, m), of 1.20 to 1.34 (10H, m), 1,38 is 1.58 (4H, m), 1,84-of 1.93 (2H, m), 2,39-to 2.42 (4H, m), 2.63 in (1H, d, J=16.4 Hz), 2.91 in (1H, d, J=16.4 Hz), 3,01 (1H, DD, J=9,4, to 13.8 Hz), 3,20 (1H, d, J=8.0 Hz), 3.27 to and 3.31 (1H, m), 3,83 (3H, s), to 4.73 (1H, DD, J=4,8 9,4 Hz), 5,48-of 5.53 (2H, m), 6.87 in-6,89 (1H, m), 7,10-7,13 (2H, m), 7,14-7,34 (3H, m), 7,50-7,52 (2H, m).

The above connection 62 synthesized using compounds 62-6 in stage 1-13 General method of obtaining 1. Connection 62-6 synthesize the following stages, based on the connection 62-1.

The synthesis of compounds 62-6

a) Synthesis of compounds 62-2

The triethylamine (32,3 ml, 232 mmol) and N-(benzyloxycarbonyloxy)succinimide (57,8 g, 232 mmol) are added to the suspension (2.5 l) tert-butyl ester of L-tyrosine (50.0 g, 211 mmol) in anhydrous dichloromethane and the mixture is stirred at room temperature for 20 hours. The reaction solution was sequentially washed with saturated aqueous ammonium chloride (1.5 l), saturated aqueous sodium bicarbonate (1.5 l) and saturated salt solution (2.0 l). After separating the organic layer from the water and drying with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, thus obtaining the connection 62-2 (82.5 g) as a colourless oil.

Physico-chemical properties of compounds 62-2

Molecular weight: 371.

ESI (LC/MS, method of positive ions) 372 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.41 (9H, s), 2,86-3,10 (2H, m), 4,36-4,56 (1H, m), is 5.06 (1H, d, J=12,5 Hz), 5,11 (1H, d, J=12,5 Hz), 5,26-5,31 (1H, m)6,00 (1H, users), 6,69 (2H, d, J=8.5 Hz), 6,98 (2H, d, J=,5 Hz), 7,25-the 7.43 (5H, m).

b) Synthesis of compounds 62-3

Anhydrous pyridine (88,5 ml of 1.09 mol) are added to a solution (400 ml) connections 62-2 (81.3 g) in anhydrous dichloromethane and the mixture is cooled to 0-5°C. Then there are added dropwise triftormetilfullerenov anhydride (43,0 ml, 262 mmol) and the mixture was stirred at the same temperature for 2 hours. To the reaction solution was added water (800 ml) and dichloromethane (1 l) and the organic layer washed sequentially with 0.5 N. aqueous sodium hydroxide solution (650 ml), water (800 ml), 1 N. hydrochloric acid (2×1 l) and water (1 l). The organic layer is dried with anhydrous sodium sulfate and concentrated, thus obtaining the connection 62-3 (105,9 g) as a milky white solid.

Physico-chemical properties of compounds 62-3

Molecular weight: 503.

ESI (LC/MS, method of positive ions) 504 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.37 (9H, s), 3,10 (2H, d, J=6,5 Hz)to 4.52 (1H, dt, J=7,5, 6.5 Hz), 5,07 (1H, d, J=12,5 Hz), 5,12 (1H, d, J=12,5 Hz), and 5.30 (1H, d, J=7.5 Hz), 7,16 (2H, d, J=9.0 Hz), 7.23 percent (2H, d, J=9.0 Hz), 7,30-the 7.43 (5H, m).

C) Synthesis of compounds 62-4

Connection 62-3 (5.0 g), 3-methoxyphenylalanine acid (to 2.57 g of 16.9 mmol) and potassium carbonate (2,33 g and 16.9 ml) suspended in anhydrous toluene (100 ml) and to the suspension is added under nitrogen atmosphere to face the Akis(triphenylphosphine)palladium (276 mg, 0,239 mmol). After stirring the mixture at 90°C for 17 hours in a stream of nitrogen, the reaction mixture was filtered using celite and the residue is washed with ethyl acetate (150 ml). The filtrate is successively washed with 0.5 N. aqueous sodium hydroxide solution (150 ml), water (150 ml), 1 N. hydrochloric acid (150 ml), water (150 ml) and saturated salt solution (150 ml). The organic layer is dried with anhydrous sodium sulfate and concentrated, thus obtaining the connection 62-4 (5,62 g) without further purification in the form of a light brown oil.

Physico-chemical properties of compounds 62-4

Molecular weight: 461.

ESI (LC/MS, method of positive ions) 462 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.41 (9H, s), of 3.12 (2H, d, J=6.0 Hz), 3,85 (3H, s), of 4.57 (1H, dt, J=8.0 a, 6,0 Hz), to 5.08 (1H, d, J=12,5 Hz)to 5.13 (1H, d, J=12,5 Hz), 5,31 (1H, d, J=8.0 Hz), 6,86-6,91 (1H, m), 7,09-7,51 (12H, m).

d) Synthesis of compounds 62-5

The catalyst, 10% palladium-on-coal (700 mg) are added to a solution (100 ml) connections 62-4 (5,52 g) in methanol and the mixture is stirred at room temperature for 2 days in a stream of hydrogen (balloon). The reaction mixture was filtered through celite and the residue washed with methanol (30 ml). The oil obtained by concentration of the filtrate, dissolved in ethyl acetate (100 ml) and sequentially extracted with 1 N. hydrochloric KIS the Auteuil (100 ml), water (100 ml) and 0.1 G. of hydrochloric acid (100 ml). The aqueous layer and the layer of 0.1 G. of hydrochloric acid are combined and regulate pH to 8.0 with saturated aqueous solution of sodium bicarbonate. The solution is extracted with ethyl acetate (100 ml) and after washing the organic layer with water (50 ml), dried with anhydrous sodium sulfate and concentrated, thus obtaining the connection 62-5 (2,43 g) as a colourless oil.

Physico-chemical properties of compounds 62-5

Molecular weight: 327.

ESI (LC/MS, method of positive ions) 328 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: of 1.44 (9H, s), is 2.88 (1H, DD, J=13,5, 8.0 Hz), is 3.08 (1H, DD, J=13,5, 5,5 Hz)to 3.64 (1H, DD, J=8.0 a, 5,5 Hz), 3,86 (3H, s), 6.89 in (1H, DDD, J=8.0 a, 2,5, 1.0 Hz), 7,11 (1H, DD, J=2.5 and 1.5 Hz), 7,17 (1H, DDD, J=8.0 a, 1,5, 1.0 Hz), 7,29 (2H, d, J=8.5 Hz), 7,35 (1H, t, J=8.0 Hz), 7,35 (2H, d, J=8,5 Hz).

e) Synthesis of compounds 62-6

The solution (100 ml) connections 62-5 (2,43 g) in ethyl acetate is cooled to 0-5°and to it add 4 N. hydrochloric acid in ethyl acetate (2,80 ml, and 11.2 mmol) followed by stirring of the mixture at the same temperature for 1 hour. The precipitated powder is collected by filtration Millipore filter (FR-20) and after washing it with ethyl acetate (20 ml), dried under reduced pressure using a vacuum pump, while receiving the connection 62-6 (2.6 g) as colorless powder.

Physico-chemical properties of compounds 62-6

Molecular weight: 327.

ESI (LC/MS, method of positive ions) 328 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 1.45 (9H, s), up 3.22 (2H, d, J=7,0 Hz), of 3.84 (3H, s), is 4.21 (1H, t, J=7.0 Hz), 6,92 (1H, DDD, J=8.0 a, 2,5, 1.0 Hz), 7,14 (1H, DD, J=2.5 and 1.5 Hz), 7,19 (1H, DDD, J=8.0 a, 1,5, 1.0 Hz), to 7.35 (1H, t, J=8.0 Hz), 7,37 (2H, d, J=8.5 Hz), 7,63 (2H, d, J=8,5 Hz).

Example 49

Physico-chemical properties of compounds 63

Molecular weight: 719.

ESI (LC/MS, method of positive ions) 720 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,08 is 1.20 (4H, m), of 1.20 to 1.34 (10H, m), 1,38 is 1.58 (4H, m), 1,86-of 1.92 (2H, m), 2,32-to 2.42 (4H, m), 2,61 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), 3.04 from (1H, DD, J=9,4, of 14.2 Hz), 3,20 (1H, d, J=8.0 Hz), 3,30-of 3.31 (1H, m), and 4.75 (1H, DD, J=4,6, and 9.4 Hz), the 5.45 of 5.53 (2H, m), of 7.36 (2H, d, J=8,4 Hz), EUR 7.57 (2H, d, J=8,4 Hz), 7,62-7,63 (2H, m), a 7.85-7,87 (2H, m).

Example 50

Physico-chemical properties of compounds 64

Molecular weight: 685.

ESI (LC/MS, method of positive ions) 686 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.6 Hz), 1,15-1,37 (14H, m), 1,42-of 1.57 (4H, m), 1,89 of 1.99 (2H, m), 2,33 is 2.43 (4H, m), 2,61 (1H, d, J=16.0 Hz), 2,92 (1H, d, J=16.0 Hz), 2,98 (1H, DD, J=Hz 9,2,14,0), 3,20-of 3.27 (2H,m), and 4.68 (1H, DD, J=4,4, 9,2 Hz), 5,52-to 5.58 (2H, m), 6,65 of 6.68 (1H, m), 6.73 x-6,76 (1H, m), 6,78-6,83 (1H, m), 6,93 (2H, d, J=8.6 Hz), 7,25 (2H, d, J=8.6 Hz), 7,29-7,34 (1H, m).

Example 51

Physicochemical properties of compound 65

Molecular weight: 669.

ESI (LC/MS, method of positive ions) 670 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,10-1,22 (4H, m), 1,22-of 1.32 (10H, m), 1,38 is 1.58 (4H, m), 1,87 is 1.96 (2H, m), 2,32-to 2.42 (4H, m)of 2.64 (1H, d, J=16.0 Hz), 2,92 (1H, d, J=16.0 Hz), 3.04 from (1H, DD, J=9,4, to 13.6 Hz), up 3.22 (1H, d, J=8.0 Hz), 3.27 to 3.30 levels (1H, m), to 4.73 (1H, DD, J=4,6, and 9.4 Hz), 5,51-to 5.56 (2H, m), 7,13 - of 7.25 (2H, m), 7,30-7,34 (3H, m), 7,43-7,47 (3H, m).

Example 52

Physico-chemical properties of compounds 66

Molecular weight: 669.

ESI (LC/MS, method of positive ions) 670 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,08 is 1.20 (4H, m), of 1.20 to 1.34 (10H, m), 1,40 is 1.58 (4H, m), 1.85 to of 1.93 (2H, m), 2,32-to 2.42 (4H, m), 2,61 (1H, d, J=16.4 Hz), 2,90 (1H, d, J=16.4 Hz), 3,02 (1H, DD, J=9,4, to 13.8 Hz), 3,20 (1H, d, J=8.0 Hz), 3.27 to 3.30 levels (1H, m), 4,74 (1H, DD, J=4,8, and 9.4 Hz), the 5.45 to 5.55 (2H, m), 7,02-7,07 (1H, m), 7,31-7,33 (3H, m), 7,41-7,44 (2H, m), 7,53-of 7.55 (2H, m).

Example 53

Physico-chemical properties of compounds 67

Molecular weight: 710.

ESI (LC/MS, method of positive ions) 711 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1.18 to 1,37 (14H, m), 1,43 is 1.58 (4H, m), 1,90 of 1.99 (2H, m), 2,32-to 2.42 (4H, m)2,60 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), 2.95 and is 3.15 (1H, m), 3,20 (6H, s), 3,22-3,30 (2H, m), and 4.68 (1H, DD, J=4,4, 9,2 Hz), 5,47-5,61 (2H, m), 6,88-of 6.90 (2H, m), 7,01-7,05 (2H, m), 7.23 percent (2H, d, J=8.6 Hz), 7,33 (2H, d,J=8.6 Hz).

Example 54

Physico-chemical properties of compounds 68

Molecular weight: 694.

ESI (LC/MS, method of positive ions) 695 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,11-1,20 (4H, m)of 1.20 and 1.35 (10H, m), 1,38 is 1.58 (4H, m), 1.85 to was 1.94 (2H, m), 2,30-to 2.42 (4H, m), 2,62 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), 3,00 (1H, DD, J=9,6, OF 14.0 HZ), of 3.13 (6H, s), 3,21 (1H, d, J=8,4 Hz), 3,26-3,30 (1H, m), to 4.73 (1H, DD, J=4,4, 9.6 Hz), the 5.45 to 5.56 (2H, m), 7,21 (2H, d, J=8,8 Hz), 7,28 (2H, d, J=8,2 Hz), 7,51 (2H, d, J=8,2 Hz), a 7.62 (2H, d, J=8,8 Hz).

Example 55

Physico-chemical properties of compounds 69

Molecular weight: 666.

ESI (LC/MS, method of positive ions) 667 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,12-1,22 (4H, m), 1,22-of 1.35 (10H, m), 1,40 is 1.58 (4H, m), 1,90-2,00 (2H, m), 2,31-to 2.42 (4H, m), 2,65 (1H, d, J=16.4 Hz), 2,90-2,95 (2H, m), 3,13-3,16 (1H, m), 3,23 (1H, d, J=8.0 Hz), with 4.64 (1H, DD, J=4,6, and 9.0 Hz), 5,52-to 5.56 (2H, m), 6,78-PC 6.82 (1H, m), 6,97-7,00 (2H, m), 7,02-was 7.08 (4H, m), 7,16-7,20 (2H, m).

Example 56

Physico-chemical properties of compounds 70

Molecular weight: 692.

ESI (LC/MS, method of positive ions) 693 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,16-of 1.35 (14H, m), 1,44 is 1.58 (4H, m), 1,87 of 1.99 (2H, m), 2,34 at 2.45 (4H, m)2,60 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), of 3.00 (1H, DD, J=9,4, of 13.8 Hz), 3,21 (1H, d, J=8,8 Hz), 3.25 to and 3.31 (1H, m), 470 (1H, DD, J=4,4, 9.4 Hz), 5,51-5,59 (2H, m), of 6.99 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,30 (2H, d, J=8,8 Hz), 7,69 (2H, d, J=8,8 Hz).

Example 57

Physico-chemical properties of compounds 71

Molecular weight: 676.

ESI (LC/MS, method of positive ions) 677 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,08 is 1.20 (4H, m)of 1.20 and 1.35 (10H, m), 1,40 is 1.58 (4H, m), 1,84-of 1.92 (2H, m), 2,32 is 2.44 (4H, m), of 2.56 (1H, d, J=16.0 Hz), 2,88 (1H, d, J=16.0 Hz), 3.04 from (1H, DD, J=9,4, to 13.8 Hz), 3,18 (1H, d, J=8,4 Hz), 3,31-to 3.34 (1H, m), and 4.75 (1H, DD, J=4,8, and 9.4 Hz), the 5.45 of 5.53 (2H, m), of 7.36 (2H, d, J=8,4 Hz), 7,60 (2H, d, J=8,4 Hz), 7,79-7,81 (4H, m).

Example 58

Physico-chemical properties of compounds 72

Molecular weight: 660.

ESI (LC/MS, method of positive ions) 661 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1.18 to 1.39 in (14H, m), 1,45-is 1.51 (4H, m), 1,92 e 2.06 (2H, m), of 2.38-2.49 USD (4H, m), 2,53 (1H, d, J=16.0 Hz), 2,86 (1H, d, J=16.0 Hz), to 2.94 (1H, DD, J=8,8, of 14.0 Hz), 3,17-of 3.23 (6H, m), 3,85-a 3.87 (4H, m)and 4.65 (1H, DD, J=4,6, 8,8 Hz), 5,49-5,62 (2H, m), 7,02 (2H, d, J=8,8 Hz), 7,20 (2H, d, J=8,8 Hz).

Example 59

Physico-chemical properties of compounds 73

Molecular weight: 682.

ESI (LC/MS, method of positive ions) 683 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,12-of 1.20 (4H, m), 1,20-to 1.38 (10H, m), 1,42 is 1.58 (4H, m), 1,86-of 1.95 (2H, m), 2,32 is 2.43 (4H, m), 2,58 (1H, d, J=16.0 G is), 2,89 (1H, d, J=16.0 Hz), to 3.02 (1H, DD, J=9,2, 14.4 Hz), 3,19 (1H, d, J=8.0 Hz), 3.27 to and 3.31 (1H, m), of 3.94 (3H, s), 4,74 (1H, DD, J=4,8, and 9.2 Hz), 5,46-to 5.56 (2H, m), 6.87 in (1H, d, J=8.6 Hz), 7,32 (2H, d, J=8,2 Hz), 7,49 (2H, d, J=8,2 Hz), 7,92 (1H, DD, J=2,4, 8.6 Hz), a 8.34 (1H, d, J=2,4 Hz).

Example 60

Physico-chemical properties of compounds 74

Molecular weight: 758.

ESI (LC/MS, method of positive ions) 759 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), of 1.10-1.20 (4H, m)of 1.20 and 1.35 (10H, m), 1,38 is 1.58 (4H, m), 1,83-of 1.92 (2H, m), 2,32-to 2.42 (4H, m), 2,59 (1H, d, J=16.0 Hz), 2,71 (6H, s), 2,89 (1H, d, J=16.0 Hz), totaling 3.04 (1H, DD, J=9,2, to 13.8 Hz), 3,19 (1H, d, J=8.0 Hz), 3,30-to 3.35 (1H, m), was 4.76 (1H, DD, J=4,4, 9,2 Hz), 5,49-of 5.53 (2H, m), 7,37 (2H, d, J=7,6 Hz), a 7.62 (2H, d, J=7,6 Hz), 7,82-7,87 (4H, m).

Example 61

Physico-chemical properties of compounds 75

Molecular weight: 680.

ESI (LC/MS, method of positive ions) 681 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.88 (3H, t, J=5.6 Hz), 1,14-1,37 (14H, m), 1,42 is 1.58 (4H, m), 1,88 of 1.99 (2H, m), 2,31-to 2.42 (4H, m), 2,62 (1H, d, J=16.0 Hz), 2,89-2,96 (2H, m), 3,14 is 3.23 (2H, m)of 3.25 (3H, C)and 4.65 (1H, DD, J=4,6, and 9.0 Hz), 5,48-5,67 (2H, m), 6.89 in-6,97 (3H, m), 6,92-6,97 (2H, m), 6,97-7,10 (2H, m), 7,11 - of 7.25 (2H, m).

Example 62

Physico-chemical properties of compounds 76

Molecular weight: 653.

ESI (LC/MS, method of positive ions) 654 (M+H+)

1H-NMR (in methanol d-4) the magnitude of the chemical shift is δ : to 0.89 (3H, t, J=7.0 Hz), 1,12-1,22 (4H, m), 1,22-to 1.38 (10H, m), 1,42-of 1.56 (4H, m), 1,88-of 1.97 (2H, m), 2,32 is 2.43 (4H, m), 2,50 (1H, d, J=16.0 Hz), 2,85 (1H, d, J=16.0 Hz), 3,06 (1H, DD, J=9,6, of 14.2 Hz), 3,18 (1H, d, J=8,4 Hz), 3,31-3,37 (1H, m), of 4.77 (1H, DD, J=4,6, and 9.6 Hz), 5,47-5,59 (2H, m), the 7.43 (2H, d, J=8,4 Hz), to 7.64 (2H, d, J=8,4 Hz), 9,04 (2H, s), 9,11 (1H, s).

Example 63

Physico-chemical properties of compounds 77

Molecular weight: 697.

ESI (LC/MS, method of positive ions) 698 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.88 (3H, t, J=7.0 Hz), 1,07-of 1.18 (4H, m), of 1.18 to 1.34 (10H, m), 1,34 is 1.58 (4H, m), 1,82-of 1.92 (2H, m), 2,29-to 2.42 (4H, m)of 2.50 (3H, s), 2,62 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), of 3.00 (1H, DD, J=9,6, of 14.2 Hz), 3,21 (1H, d, J=7,6 Hz), 3,26-of 3.31 (1H, m), to 4.73 (1H, DD, J=4,8, and 9.6 Hz), 5,44-of 5.53 (2H, m), 7,27-to 7.32 (4H, m), 7,50-rate of 7.54 (4H, m).

Example 64

Physicochemical properties of compound 78

Molecular weight: 682.

ESI (LC/MS, method of positive ions) 683 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,12-to 1.21 (4H, m), to 1.21 to 1.37 (10H, m), 1.41 to was 1.58 (4H, m), 1,86 is 1.96 (2H, m), 2,32 is 2.43 (4H, m), 2,52 (1H, d, J=16.4 Hz), 2,86 (1H, d, J=16.4 Hz), 3,05 (1H, DD, J=9,3, a 13.9 Hz), 3,17 (1H, d, J=8,3 Hz), 3,32-to 3.36 (1H, m)to 3.99 (3H, s), was 4.76 (1H, DD, J=4,9, and 9.3 Hz), 5,46-to 5.57 (2H, m), 7,40 (2H, d, J=8,3 Hz), a 7.62 (2H, d, J=8,3 Hz), 7,81-of 7.82 (1H, m), 8,28-8,29 (1H, m), 8,46 (1H, s).

Example 65

Physicochemical properties of compound 79

Molecular weight: 670.

ESI (LC/MS, method p is a positive ion) 671 (M+H +)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,15-1,36 (14H, m), 1.41 to was 1.58 (4H, m), 1,87-to 1.98 (2H, m), of 2.23 (3H,s), 2,33 at 2.45 (7H, m), 2,58 (1H, d, J=16.0 Hz), 2,88 (1H, d, J=16.0 Hz), 3,03 (1H, DD, J=9,2, of 14.0 Hz), 3,21 (1H, d, J=8,4 Hz), 3,30-to 3.34 (1H, m), to 4.73 (1H, DD, J=4,4, 9,2 Hz), 5,49-the ceiling of 5.60 (2H, m), 7,24 (1H, d, J=8,4 Hz), 7,34 (2H, d, J=8,4 Hz).

Example 66

Physico-chemical properties of compounds 80

Molecular weight: 729.

ESI (LC/MS, method of positive ions) 730 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.8 Hz), 1,10-1,19 (4H, m), 1,19-of 1.33 (10H, m), 1,34 is 1.58 (4H, m), 1.85 to of 1.93 (2H, m), 2,31-to 2.42 (4H, m), 2,59 (1H, d, J=16.6 Hz), 2,88 (1H, d, J=16.6 Hz), 3.04 from (1H, DD, J=9,6, of 14.0 Hz), 3,14 (3H, s), 3,20 (1H, d, J=7,6 Hz), 3,31-to 3.35 (1H, m), was 4.76 (1H, DD, J=4,4, 9.6 Hz), the 5.45 to 5.56 (2H, m), 7,37 (2H, d, J=8,2 Hz), a 7.62 (2H, d, J=8,2 Hz), 7,86 (2H, d, J=8.6 Hz), of 8.00 (2H, d, J=8.6 Hz).

Example 67

Physico-chemical properties of compounds 81

Molecular weight: 683.

ESI (LC/MS, method of positive ions) 684 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.2 Hz), 1,08 is 1.20 (4H, m), 1,20-1,36 (10H, m), 1,39 is 1.58 (4H, m), 1,87-of 1.95 (2H, m), 2,32 at 2.45 (4H, m), 2,53 (1H, d, J=16.4 Hz), 2,86 (1H, d, J=16.4 Hz), 3,03 (1H, DD, J=9,6, of 14.2 Hz), 3,19 (1H, d, J=8.0 Hz), 3,31-to 3.34 (1H, m), Android 4.04 (3H, s), and 4.75 (1H, DD, J=4,6, and 9.6 Hz), 5,46-to 5.56 (2H, m), 7,37 (2H, d, J=8,4 Hz), 7,55 (2H, d, J=8,4 Hz), 8,79 (2H, s).

Example 68

Physicochemical t the VA connection 82

Molecular weight: 648.

ESI (LC/MS, method of positive ions) 649 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,48 is 1.58 (4H, m), 1.93 and-2,02 (2H, m), 2.05 is-of 2.16 (2H, m), of 2.25 (1H, d, J=16.0 Hz), 2,43 (4H, t, J=7.5 Hz), 2,71 (1H, d, J=16.0 Hz), 2,90 (1H, DD, J=14,0, 9.5 Hz), 3,10-of 3.25 (4H, m), 4,08 (2H, t, J=5.5 Hz), to 4.62 (1H, DD, J=a 9.5 and 4.5 Hz), 5,47-5,64 (2H, m), at 6.84 (2H, d, J=8.5 Hz), 7,16 (2H, d, J=8,5 Hz).

Example 69

Physico-chemical properties of compounds 83

Molecular weight: 688.

ESI (LC/MS, method of positive ions) 689 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,21-of 1.40 (14H, m), 1,47 is 1.58 (4H, m), 1,94-2,03 (2H, m), 2,00-2,30 (4H, m), 2,43 (4H, t, J=7.5 Hz), 2.49 USD (1H, d, J=16.0 Hz), of 2.81 (1H, d, J=16.0 Hz), 2,89 (3H, s), with 2.93 (1H, DD, J=14,0, 9.0 Hz), 3,17 (1H, d, J=8.0 Hz), 3,19 (1H, DD, J=14,0, 5.0 Hz), 3.27 to 3,44 (4H, m), 4,60-of 4.67 (1H, m), 4,63 (1H, DD, J=9,0, 5.0 Hz), 5,47-the 5.65 (2H, m), of 6.90 (2H, d, J=8,5 Hz), 7,18 (2H, d, J=8,5 Hz).

Example 70

Physicochemical properties of compound 84

Molecular weight: 676.

ESI (LC/MS, method of positive ions) 677 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,21-1,38 (16H, m), 1,47 is 1.58 (4H, m), 1,94-2,03 (2H, m), 2,15 was 2.25 (2H, m), 2,22 (1H, d, J=16.0 Hz), 2,43 (4H, t, J=7.5 Hz), 2,71 (1H, d, J=16.0 Hz), 2,89 (1H, DD, J=14,0, 9.5 Hz), 2,90 (6H, s), 3,10 (1H, d, J=8.0 Hz), up 3.22 (1H, DD, J=14,0, and 4.5 Hz), 4,08 (2H, t, J=5.5 Hz), 4,63 (1H, DD, J=a 9.5 and 4.5 Hz), 5,47-5,64 (2H, m), 6,83 (2H, d J=8.5 Hz), 7,16 (2H, d, J=8,5 Hz).

Example 71

Physico-chemical properties of compounds 85

Molecular weight: 682.

ESI (LC/MS, method of positive ions) 683 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,19-1,36 (14H, m), USD 1.43-of 1.57 (4H, m), 1.93 and-2,02 (2H, m), 2,37 is 2.44 (4H, m), 2,53 (1H, d, J=16.0 Hz), 2,87 (1H, d, J=16.0 Hz), of 2.92 (1H, DD, J=14,0, 9.0 Hz), 3,18 (1H, d, J=8.0 Hz), 3,19 (1H, DD, J=14,0, and 4.5 Hz), of 4.66 (1H, DD, J=9,0, 4.5 Hz), to 5.17 (2H, s), the 5.45 5,62 (2H, m), 6,93 (2H, d, J=8.5 Hz), 7,17 (2H, d, J=8.5 Hz), 7,63 (1H, ushort, J=8.0 Hz), 8,13 (1H, userd, J=8.0 Hz), 8,58 (1H, users), to 8.70 (1H, users).

Example 72

Physico-chemical properties of compounds 86

Molecular weight: 704.

ESI (LC/MS, method of positive ions) 705 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,21-1,39 (14H, m), 1,47 is 1.58 (4H, m), 1,95-2,03 (2H, m), 2.40 a is 2.46 (4H, m), 2,58 (1H, d, J=15,5 Hz), 2,89 (1H, DD, J=14,0, 10,0 Hz), 3,03 (1H, d, J=7,0 Hz), 3,10-of 3.48 (8H, m), 3,86-to 3.92 (4H, m), 4,29-4,39 (2H, m), 4,63 (1H, DD, J=10,0, 4.0 Hz), 5,49-to 5.66 (2H, m), 6.87 in (2H, d, J=8.5 Hz), 7,19 (2H, d, J=8,5 Hz).

Example 73

Physicochemical properties of compound 87

Molecular weight: 703.

ESI (LC/MS, method of positive ions) 704 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,22-1,39 (14H, m), 1,47-to 1.59 (4H, m), 1,95-2,02 (2H, m), 2,34 (1H, d, J=16.0 Hz), 2,43 (4H, t, J=7.5 Hz), 2,3 (1H, d, J=16.0 Hz), 2,86-2,96 (7H, m), 3,12 (1H, d, J=8.0 Hz), 3,16-up 3.22 (5H, m), of 4.13 (2H, t, J=5.0 Hz), br4.61 (1H, DD, J=9,0, 5.0 Hz), 5,47-the 5.65 (2H, m), 6,83 (2H, d, J=8.5 Hz), 7,16 (2H, d, J=8,5 Hz).

Example 74

Physicochemical properties of compound 88

Molecular weight: 739.

ESI (LC/MS, method of positive ions) 740 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1.18 to 1,38 (16H, m), 1,46 is 1.58 (4H, m), 1,92-2,02 (2H, m), 2,10-of 2.24 (2H, m), 2,43 (4H, t, J=7.5 Hz), to 2.67 (1H, d, J=16.0 Hz), 2,89 (1H, DD, J=14,0, 9.5 Hz), 3,06-3,11 (1H, m), 3,21-3,30 (2H, m), 4.09 to (2H, ushort, J=5.0 Hz), 4,30 (2H, s), to 4.62 (1H, DD, J=a 9.5 and 4.5 Hz), 5,47-5,62 (2H, m), PC 6.82 (2H, d, J=8.5 Hz), to 7.15 (2H, d, J=8.5 Hz), of 7.48-7,56 (1H, m), to 7.99 (1H, userd, J=7.5 Hz), 8,61 (1H, users), 8,66 (1H, users).

Example 75

Physicochemical properties of compound 89

Molecular weight: 731.

ESI (LC/MS, method of positive ions) 732 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,48 is 1.60 (4H, m), 1,92-of 2.09 (4H, m), 2,43 (4H, t, J=7.5 Hz), 2,77 (3H, s), 2,83 are 2.98 (8H, m), 3,11-3,26 (7H, m), Android 4.04 (2H, ushort, J=5.5 Hz), 4,63 (1H, DD, J=9,0, 4.5 Hz), 5,43-5,63 (2H, m), for 6.81 (2H, d, J=8.5 Hz), 7,13 (2H, d, J=8,5 Hz).

Example 76

Physico-chemical properties of compounds 90

Molecular weight: 616.

ESI (LC/MS, method of positive ions) 617 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H,t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,48-to 1.59 (4H, m), 1,90-2,00 (2H, m), 2,43 (4H, t, J=7.5 Hz), 2,50 (1H, d, J=16.0 Hz), 2,87 (1H, d, J=16.0 Hz), 2,95 (1H, DD, J=14,0, 9.5 Hz), 3,17 (1H, d, J=8.0 Hz), 3,24 (1H, DD, J=14,0, and 4.5 Hz), and 4.68 (1H, DD, J=a 9.5 and 4.5 Hz), 5,44-the ceiling of 5.60 (2H, m), to 6.95 (2H, d, J=8.5 Hz), 7,25 (2H, d, J=8,5 Hz).

Example 77

Physicochemical properties of compound 91

Molecular weight: 826.

ESI (LC/MS, method of positive ions) 827 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.88 (3H, t, J=6.5 Hz), 1,15-1,35 (14H, m), 1,40-of 1.55 (4H, m), 1.85 to a 2.00 (2H, m), 2,34-to 2.40 (4H, m), 2,53 (1H, d, J=16.0 Hz), 2,87 (1H, d, J=16.0 Hz), 2,98 (1H, DD, J=14,0, 9.0 Hz), 3,20 (1H, d, J=8.0 Hz), 3,21 (1H, DD, J=14,0, and 4.5 Hz), 4,18-4.26 deaths (3H, m), 4,36 (2H, d, J=6.5 Hz), of 4.67 (1H, DD, J=9,0, 4.5 Hz), the 5.45 5,63 (2H, m), 7,17 (4H, s), 7,30 (2H, t, J=7.5 Hz), 7,39 (2H, t, J=7.5 Hz), the 7.65 (2H, d, J=7.5 Hz), 7,79 (2H, d, J=7.5 Hz).

Example 78

Physico-chemical properties of compounds 92

Molecular weight: 668.

ESI (LC/MS, method of positive ions) 669 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,19-1,39 (14H, m), 1,48 is 1.58 (4H, m), 1.93 and-2,04 (2H, m), is 2.44 (4H, t, J=7.5 Hz), 2,61 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), only 2.91 (3H, s), 2,96 (1H, DD, J=14,5, 9.0 Hz), 3,17-3,24 (2H, m), of 4.66 (1H, DD, J=9,0, 4.5 Hz), 5,46-5,64 (2H, m), to 7.15 (2H, d, J=8.5 Hz), 7,20 (2H, d, J=8,5 Hz).

Example 79

Physico-chemical properties of compounds 93

Molecular weight: 632.

ESI (LC/MS method a positive IO is s) 633 (M+H +)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,45 is 1.58 (4H, m), 1,90-2,00 (2H, m), 2,10 (3H, s), 2,43 (4H, t, J=7.5 Hz), 2,59 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), 2,95 (1H, DD, J=14,0, 9.0 Hz), 3,15-up 3.22 (2H, m), of 4.66 (1H, DD, J=9,0, 4.5 Hz), the 5.45 ceiling of 5.60 (2H, m), to 7.15 (2H, d, J=8.5 Hz), 7,46 (2H, d, J=8,5 Hz).

Example 80

Physico-chemical properties of compounds 94

Molecular weight: 604.

ESI (LC/MS, method of positive ions) 605 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,20-1,40 (14H, m), 1,48-to 1.59 (4H, m), 1.93 and-2,02 (2H, m), 2.40 a is 2.46 (4H, m)to 2.55 (1H, d, J=16.5 Hz), 2,94 was 3.05 (2H, m), 3,10 -, and 3.16 (2H, m), Android 4.04 (2H, C), 4,70 (1H, DD, J=a 9.5 and 4.5 Hz), 5,50-the 5.65 (2H, m), 7,33 (4H, s).

Example 81

Physico-chemical properties of compounds 95

Molecular weight: 632.

ESI (LC/MS, method of positive ions) 633 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,48-to 1.59 (4H, m), 1,96-2,04 (2H, m), is 2.44 (4H, t, J=7.5 Hz), to 2.55 (1H, d, J=16.0 Hz), 2,87 (1H, d, J=16.0 Hz), of 3.00 (1H, DD, J=13,5, 9.0 Hz), 3,16-3,30 (2H, m), and 4.68 (1H, DD, J=9,0, 4.5 Hz), 5,48-of 5.68 (2H, m), 7,18 (2H, d, J=8.0 Hz), 7,34 (2H, d, J=8.0 Hz).

Example 82

Physico-chemical properties of compounds 96

Molecular weight: 714.

ESI (LC/MS, method of positive ions) 715 (M+H+)

1H-NMR (in methanol d-4) the value of Henichesk the th shift δ : to 0.89 (3H, t, J=6.5 Hz), 1,15-1,33 (14H, m)of 1.41 (3H, t, J=7.0 Hz), 1,46-of 1.56 (4H, m), 1.85 to 1,95 (2H, m), 2,37 is 2.46 (4H, m), 2,52 (1H, d, J=16.0 Hz), 2,88 (1H, d, J=16.0 Hz), is 3.08 (1H, DD, J=14,0, 9.5 Hz), 3,17 (1H, d, J=8.0 Hz), to 3.38 (1H, DD, J=14,0, and 4.5 Hz), 4,42 (2H, square, J=7,0 Hz), 4,79 (1H, DD, J=a 9.5 and 4.5 Hz), 5,42-the ceiling of 5.60 (2H, m), 7,47 (2H, d, J=8.5 Hz), 7,82 (2H, d, J=8.5 Hz), which is 9.09 (1H, s).

Example 83

Physicochemical properties of compound 97

Molecular weight: 576.

ESI (LC/MS, method of positive ions) 577 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,20-1,40 (14H, m), 1,45 is 1.58 (4H, m), 1.93 and-2,03 (2H, m), 2,41 is 2.46 (4H, m), of 2.51 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), of 3.13 (1H, DD, J=14,0, 9.5 Hz), 3,18 (1H, d, J=8.0 Hz), 3,39 (1H, DD, J=14,0, 5.0 Hz), 4,78 (1H, DD, J=9,5, 5.0 Hz), 5,46-5,64 (2H, m), to 7.61 (1H, DD, J=8.0 a, 5,5 Hz), of 8.06 (1H, d, J=8.0 Hz), charged 8.52 (1H, d, J=5.5 Hz), to 8.57 (1H, s).

Example 84

Physicochemical properties of compound 98

Molecular weight: 665.

LC/MS (ESI, method of positive ions) 666 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δas 0.96 (6H, d, J=7,0 Hz), 1,22-1,46 (10H, m), 1,48 is 1.75 (8H, m), 1,75-1,90 (1H, m), 1.93 and is 2.00 (2H, m), 2.40 a-2,48 (4H, m), 2,58 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), 2,90 (1H, DD, J=14,0, 9,0 Hz)and 3.15 (1H, DD, J=14,0, 5.0 Hz), 3,19 (1H, d, J=8.0 Hz), of 3.95 (2H, t, J=6.5 Hz), and 4.40 (2H, dt, J=47,5, 6,0 Hz), 4,63 (1H, DD, J=9,0, 5.0 Hz), the 5.45 5,61 (2H, m), 6,79 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8,5 Hz).

Example 85

Physicochemical properties of compound 99

Molecular weight: 677.

LC/MS (ESI, method of positive ions) 678 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δas 0.96 (6H, d, J=6.3 Hz), 1,26-to 1.38 (10H, m), 1,45-to 1.59 (6H, m)of 1.64 (2H, square, J=6,8 Hz), 1,78-of 1.88 (1H, m), 1,94-to 1.98 (2H, m), 2,41 is 2.46 (4H, m), 2,58 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), 2,88-of 2.93 (1H, m), and 3.16 (1H, DD, J=14,0, a 4.9 Hz), 3,19 (1H, d, J=8,3 Hz)and 3.31 (3H, s)to 3.34 (2H, t, J=6.3 Hz), of 3.95 (2H, t, J=6.3 Hz), 4,62-of 4.67 (1H, m), 5,47-5,59 (2H, m), 6,79 (2H, d, J=8,8 Hz), 7,10 (2H, d, J=8,8 Hz).

Example 86

Physico-chemical properties of compounds 100

Molecular weight: 651.

ESI (LC/MS, method of positive ions) 652 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=7.0 Hz), 1,19-1,41 (14H, m), 1,43-and 1.54 (4H, m), 1.85 to a 1.96 (2H, m), 2,30-2,39 (4H, m)of 2.64 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), 2,97 totaling 3.04 (1H, m), 3,19-3,26 (2H, m), 4,70-4,78 (1H, m), 5,44-5,59 (2H, m), 7,28-to 7.32 (3H, m), 7,42 (2H, t, J=7.5 Hz), 7,52-to 7.61 (4H, m).

Example 87

Physico-chemical properties of compounds 101

Molecular weight: 667.

ESI (LC/MS, method of positive ions) 668 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), 1,19-1,37 (14H, m), 1,44-of 1.56 (4H, m), 1.91 a-to 1.98 (2H, m), 2,36 is 2.43 (4H, m), 2,62 (1H, d, J=16.0 Hz), 2,92 (1H, d, J=16.0 Hz), 2,96 (1H, DD, J=14,0, 9.5 Hz), 3,19-3,26 (2H, m), 4,74 (1H, DD, J=9,5, 5.0 Hz), the 5.45 5,61 (2H, m), 6.87 in (2H, d, J=8.5 Hz), to 6.95 (2H, d, J=7.5 Hz), was 7.08 (1H, t, J=7.5 Hz), 7,20 (2H, d, J=8.5 Hz), 7,33 (2H, t, J=7.5 Hz).

Example 88

Physico-chemical properties of compounds 102

Molecular weight: 637.

ESI (LC/MS, method of positive ions) 638 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), 1,15-1,35 (12H, m), USD 1.43-of 1.57 (4H, m), 1,87-of 1.95 (2H, m), 2,27-2,47 (4H, m), 2,62 (1H, d, J=16.0 Hz), 2.91 in (1H, d, J=16.0 Hz), to 3.02 (1H, DD, J=14,0, 9.0 Hz), 3,21 (1H, d, J=8.0 Hz), or 3.28 (1H, DD, J=14,0, and 4.5 Hz), to 4.73 (1H, DD, J=9,0, 4.5 Hz), 5,44-the ceiling of 5.60 (2H, m), 7,27-7,33 (3H, m), 7,41 (2H, t, J=7.5 Hz), 7,51-of 7.60 (4H, m).

Example 89

Physico-chemical properties of compounds 103

Molecular weight: 653.

ESI (LC/MS, method of positive ions) 654 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: to 0.89 (3H, t, J=6.5 Hz), to 1.14 to 1.37 (12H, m), 1,44-of 1.57 (4H, m), 1.91 a is 2.00 (2H, m), 2,37 is 2.44 (4H, m), 2,62 (1H, d, J=16.0 Hz), 2,92 (1H, d, J=16.0 Hz), 2,96 (1H, DD, J=14,0, 9.0 Hz), up 3.22 (1H, d, J=8.5 Hz), up 3.22 (1H, DD, J=14,0, and 4.5 Hz), of 4.67 (1H, DD, J=9,0, 4.5 Hz), 5,46-5,64 (2H, m), 6.87 in (2H, d, J=8.5 Hz), 6,94 (2H, d, J=7.5 Hz), was 7.08 (1H, t, J=7.5 Hz), 7,20 (2H, d, J=8,5 Hz), 7,33 (2H, t, J=7.5 Hz).

Example 90

Physico-chemical properties of the compound 104

Molecular weight: 671.

ESI (LC/MS, method of positive ions) 672 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), is 0.96 (3H, t, J=7.5 Hz), 1,22-1,37 (14H, m), 1,44-to 1.59 (6H, m), 1.93 and-2,03 (2H, m), 2,15-2,22 (2H, m), is 2.44 (4H, t, J=7.5 Hz), 2.57 m (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), with 2.93 (1H, DD, J=14,0, 9.0 Hz), 3,17-3,20 (1H, m), 3,20 (1H, d, J=7.5 Hz) br4.61-of 4.66 (3H, m), 5,46-5,62 (2H, m)6,86 (2H, d, J=8.5 Hz), 7,13 (2H, d, J=8,5 Hz).

Example 91

Physico-chemical properties of compounds 105

Molecular weight: 629.

ESI (LC/MS, method of positive ions) 630 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,48-to 1.59 (4H, m), 1.93 and-2,03 (2H, m), is 2.44 (4H, t, J=7.5 Hz), 2,56 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), 2,90-of 2.97 (2H, m,), 3,18 (1H, DD, J=14,0, and 4.5 Hz), 3,19 (1H, d, J=8.0 Hz), with 4.64 (1H, DD, J=9,0, 4.5 Hz), of 4.67 (2H, d, J=2.5 Hz), 5,46-5,62 (2H, m), 6.87 in (2H, d, J=8.5 Hz), 7,14 (2H, d, J=8,5 Hz).

Example 92

Physico-chemical properties of compounds 106

Molecular weight: 657.

ESI (LC/MS, method of positive ions) 658 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), 1,20-1,40 (14H, m), 1,46-to 1.59 (4H, m), 1,89 of 1.99 (4H, m), 2,24 (1H, t, J=2.5 Hz), 2,33 is 2.46 (6H, m), 2,58 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), with 2.93 (1H, DD, J=14,0, 9.0 Hz), 3,13-up 3.22 (2H, m), was 4.02 (2H, t, J=6.0 Hz), with 4.64 (1H, DD, J=9,0, 4.5 Hz), the 5.45 5,61 (2H, m), for 6.81 (2H, d, J=8.5 Hz), 7,12 (2H, d, J=8,5 Hz).

Example 93

Physico-chemical properties of compounds 107

Molecular weight: 657.

ESI (LC/MS, method of positive ions) 658 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), 1,20-1,39 (14H, m), 1,46-to 1.59 (4H, m)of 1.75 (3H, t, J=2.5 Hz), 1,90-2,00 (2H, m), 2,39-2,48 (4H, m), 2,50-2,60 (3H, m), 2,85-2,95 (2H, m), and 3.16 (1H, DD, J=4,0, the 4.5 Hz), 3,18-up 3.22 (1H, m), of 3.97 (2H, t, J=7.0 Hz), 4,63 (1H, DD, J=9,0, 4.5 Hz), the 5.45 5,61 (2H, m), to 6.80 (2H, d, J=8.5 Hz), 7,12 (2H, d, J=8,5 Hz).

Example 94

Physicochemical properties of compound 108

Molecular weight: 714.

ESI (LC/MS, method of positive ions) 715 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=7.0 Hz), 1.26 in-1,38 (20H, m), 1,50-of 1.57 (4H, m), 1,94-2,03 (2H, m), is 2.44 (4H, t, J=7.5 Hz), to 2.55 (1H, d, J=16.0 Hz), 2,87 (1H, d, J=16.0 Hz), of 2.92 (1H, DD, J=14,0, 9.0 Hz), 3,17-3,20 (2H, m), 3,21 (4H, square, J=7.5 Hz), is 4.15 (2H, t, J=2.0 Hz)and 4.65 (1H, DD, J=9,0, 4.5 Hz), 4,84 (2H, t, J=2.0 Hz), of 5.48 (1H, DD, J=to 15.0, 9.0 Hz), 5,59 (1H, dt, J=to 15.0, 6.5 Hz), make 6.90 (2H, d, J=8.5 Hz), 7,18 (2H, d, J=8,5 Hz).

Example 95

Physico-chemical properties of compounds 109

Molecular weight: 657.

ESI (LC/MS, method of positive ions) 658 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), is 1.11 (3H, t, J=7.5 Hz), 1,20-1,38 (14H, m), 1,48-to 1.59 (4H, m), 1.93 and is 2.01 (2H, m), 2,16-of 2.26 (2H, m), is 2.44 (4H, t, J=7.0 Hz), 2,58 (1H, d, J=16.0 Hz), 2,89 (1H, d, J=16.0 Hz), of 2.92 (1H, DD, J=14,0, 9.0 Hz), 3,17 (1H, DD, J=14,0, and 4.5 Hz), 3,20 (1H, d, J=8.0 Hz), to 4.62 (2H, t, J=2.0 Hz), 4,63-of 4.66 (1H, m), the 5.45 5,62 (2H, m), 6,85 (2H, d, J=8.5 Hz), 7,13 (2H, d, J=8,5 Hz).

Example 96

Physico-chemical properties of compounds 110

Molecular weight: 727.

ESI (LC/MS, method of positive ions) 728 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical is on shift δ : of 0.90 (6H, t, J=6.5 Hz), 1,20-1,59 (28H, m), 1.93 and is 2.01 (2H, m), 2,17-of 2.23 (2H, m), is 2.44 (4H, t, J=7.0 Hz), 2,64 (1H, d, J=16.5 Hz), 2,89 (1H, d, J=16.5 Hz), of 2.92 (1H, DD, J=14,0, 9.0 Hz), 3,17 (1H, DD, J=14,0, the 4.5 Hz), 3,20 (1H, d, J=7.5 Hz), 4,63 (2H, t, J=2.0 Hz), 4,63-of 4.66 (1H, m), the 5.45 5,61 (2H, m), 6,85 (2H, d, J=8.5 Hz), 7,13 (2H, d, J=8,5 Hz).

Example 97

Physico-chemical properties of compounds 111

Molecular weight: 709.

ESI (LC/MS, method of positive ions) 710 (M+H+)

1H-NMR (in methanol d-4) the value of the chemical shift δ: of 0.90 (3H, t, J=6.5 Hz), of 1.23 (9H, s), 1,24-of 1.40 (14H, m), 1,46-to 1.59 (4H, m), 1.93 and-2,02 (2H, m), is 2.44 (4H, t, J=7.0 Hz), 2,58 (1H, d, J=16.0 Hz), 2,90 (1H, d, J=16.0 Hz), of 2.93 (1H, DD, J=14,0, 9.0 Hz), 3,19 (1H, DD, J=14,0, and 4.5 Hz), 3,20 (1H, d, J=8.0 Hz)and 4.65 (1H, DD, J=9,0, 4.5 Hz), 4,74 (2H, s), 5,51-5,61 (2H, m)6,86 (2H, d, J=8.5 Hz), to 7.15 (2H, d, J=8,5 Hz).

Example obtain 1

In the example of a 1 describes a synthetic route for obtaining compounds used in stage 1-7 in obtaining the compounds of formula (I).

Stage 2-1

8-Nonnovel acid (50 g, 0.32 mol) is added dropwise to a solution of the hydrochloride of N,O-dimethylhydroxylamine(and 63.3 g of 0.65 mol), water-soluble carbodiimide hydrochloride (WSC HCl) (124 g of 0.65 mol), 1-hydroxybenzotriazole (HOBt) (99,3 g to 0.65 mol) and N,N-diisopropylethylamine (DIPEA) (220 ml, 1.3 mol) in dichloromethane (500 mg) at 0°and the mixture is stirred at room temperature for 15 hours. The reaction solution washed the t saturated aqueous ammonium chloride (400 ml), saturated aqueous ammonium hydrogen carbonate (400 ml) and saturated salt solution (300 ml). After separating the organic layer from the water it is dried with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. Thus obtained residue is purified column chromatography (Wako-gel C-300, 500 g, Wako Pure Chemical). Compound 112 (60 g, 94%) obtained from part elyuirovaniya a mixture of hexane/ethyl acetate (20:1), in the form of a colorless oil.

Physicochemical properties of compound 112

Molecular weight: 197.

ESI (LC/MS, method of positive ions) 198 (M+H+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: 1,30-1,70 (8H, m), of 1.94 (1H, t, J=2.5 Hz), 2,19 (2H, dt, J=2,5, 7 Hz), 2,42 (2H, t, J=7.5 Hz), 3,18 (3H, s), 3,68 (3H, s).

Stage 2-2

1 M solution of n-heptylaniline in diethyl ether (100 ml, 0.1 mol) is added dropwise to a solution of the above compound 112 (7 g, 0.035 mol) in tetrahydrofuran (100 ml) at -10°and the mixture was stirred at the same temperature for 2 hours and 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and to it add additional water (100 ml) followed by stirring the mixture at room temperature for 10 minutes. The mixture was diluted with water (300 ml) and extracted twice with ethyl acetate (400 ml). Organic is Lois unite, washed with saturated salt solution and separated from the water and dried with anhydrous sodium sulfate, followed by distillation of solvent under reduced pressure. The residue is purified column chromatography (Wako-gel C-300, 250 g, Wako Pure Chemical). Compound 113 (7,8 g, 93%) is obtained from the part, elyuirovaniya a mixture of hexane/ethyl acetate (100:1), in the form of a colorless oil.

Physicochemical properties of compound 113

Molecular weight: 236.

EI-MC 236 (M+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6.5 Hz), 1,23-1,63 (18H, m), of 1.94 (1H, dt, J=0.5, and 2.5 Hz), to 2.18 (2H, dt, J=2,5, 7 Hz), a 2.36-to 2.42 (4H, m).

Stage 2-3

The above compound 113 (7,8 g 0,033 mol), ethylene glycol (18 ml, 0.33 mol) and monohydrate toluensulfonate acid (125 mg, 0.66 mmol) are added to a benzene (150 ml) and the flask attached partial condenser hot irrigation with water separator Dean-stark, followed by heating the mixture while boiling under reflux for 20 hours. After providing the reaction solution cooling capabilities reaction solution was washed with saturated aqueous sodium hydrogen carbonate (30 ml), water (50 ml) and then with saturated salt solution (50 ml). The organic layer is separated from the water and dried with anhydrous sodium sulfate and the solvent is distilled off under reduced giving the situation. Thus obtained residue is purified Mega Bond Elut SI (10 g, Barian Inc.). The connection 114 (8,9 g, 97%) obtained from part elyuirovaniya a mixture of hexane/ethyl acetate (20:1), in the form of a colorless oil.

Physico-chemical properties of compounds 114

Molecular weight: 280.

EI-MC 280 (M+)

1H-NMR (in deuterium chloroform) the magnitude of the chemical shift δ: to 0.88 (3H, t, J=6.5 Hz), 1,23-1,63 (22H, m)of 1.93 (1H, t, J=2,5 Hz)to 2.18 (2H, dt, J=2,5, 7 Hz), to 3.92 (4H, s).

The test example 1

Analysis of the replicon

Get a construction in which luciferase gene derived from Firefly, enter as a reporter gene in HCV-RNA for analysis of the number of copies of HCV-RNA. Gene luciferase injected in the form of a hybrid gene of resistance to neomycin, directly below the IRES (internal customers of the sequence of occurrence of ribosomes) gene of HCV, in accordance with the method Krieger, et al. (J. Virol. 75:4614). After synthesis of this RNA in vitro of its type in the Huh7 cell by electroporation and isolated in the form of G418-resistant clone. Cells (3-1), which contain the HCV replicon gene luciferase Firefly, suspended in MEM, Dulbecco (Gibco cat. No. 10569-010)containing 5% fetal bovine serum (Hyclone cat. No. SH30071.03), inoculant in wells of 96-well plate at the rate of 5000 cells/well and then cultured overnight at 37°C and 5% CO2. After approximately 20 hours, add the diluted test compound PR is the norm of 10 μl per well, followed by cultivation for 3 more days. Prepare two series of analytical tablets and the analysis is performed by applying a matte tablet for one series and a transparent tablet for another series. After completion of the cultivation matte tablet used for system analysis luciferase Steady-Glo (Promega cat. No. e). Namely, after adding 100 ál per well, mix by pipette 3-4 times and then keeping within 5 minutes, the luminescence is measured 1450 MicroBeta TRILUX (Wallac). The values obtained in the absence of added cells, used as background values and subtracted from all values to calculate the IC50(concentration of 50% inhibition) of the medicinal product on the basis of values of 0% inhibition for the value in the absence of added test compound.

The test example 2

The cytotoxicity test

Set to count cells 8 (Dojindo cat. No. CK04) is used to determine cytotoxicity. Specifically, 10 μl of the set to count cells 8 are added to the transparent plate and incubated for 30-60 minutes at 37°C. the Absorption at a wavelength of 450 nm and reference wavelength of 630 nm was measured 96-well plate reader. Values in the absence of cell adhesion is used as background values and subtracted from all values to calculate SS50(concentration inhibiting 50% of the cells) of the medicinal product on the basis of the magnitude of Inga the financing 0% for values in the absence of added drug.

Results examples tests 1 and 2 shown below.

Biological activity

Industrial applicability

Compounds of the present invention have a very strong activity against HCV and the inhibiting effect on the growth of HCV, and because they also exhibit only weak cytotoxicity in vitro, pharmaceutical composition containing the compound of the present invention is highly applicable as a preventive/therapeutic agent against HCV.

1. A compound selected from the group comprising the following compounds:

or its pharmaceutically acceptable salt.

2. The remedy against HCV, comprising as an active ingredient the compound according to claim 1 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of C-cyclohexylmethylamine of the general formula (I): in their free form or physiologically compatible salts possessing analgesic effect. In the general formula (I) A means hydrogen atom (H) or unsubstituted phenyl; R1 means saturated or unsaturated, branched or linear mono- or multisubstituted or unsubstituted (C1-C10)-alkyl or (C3-C10)-cycloalkyl, phenyl, naphthyl, furyl, thiophenyl or naphthyl added through unsaturated (C2-C3)-alkyl either through (C1-C3)-alkylene or ethynyl, (C3-C10)-cycloalkyl added through unsaturated (C2-C3)-alkyl or through (C1-C3)-alkylene or ethynyl, or thiophenyl added through unsaturated (C2-C3)-alkyl, either through (C1-C3)-alkylene or ethynyl, respectively, unsubstituted or mono- either multi-substituted with residues chosen independently of one another from a group comprising fluorine (F), chlorine (Cl), bromine (Br), iodine (J) atom, -OR18, -SR18, silyl, unsubstituted or mono- either multi-substituted alkyl wherein substituted of substitutes of (C1-C10)-alkyl are similar or different and are chosen from the group comprising F, Cl, and Br and wherein R18 represents H or saturated or unsaturated, branched or linear, unsubstituted (C1-C10)-alkyl; R2 and R3 mean independently of one another branches or linear saturated unsubstituted (C1-C10)-alkyl, or R2 and R3 form in common the group -CH2CH2NR6CH2CH2 wherein R6 means branched or linear (C1-C10)-alkyl; X in the formula (I) in correspondence with the subformula (1a): of the formula (I) represents or wherein B represents -OH, -OR7, H, F or Cl wherein R7 means mono- or multi-substituted phenyl added through (C1-C3)-alkylene wherein substitutes of phenyl are chosen from F and Cl and others. Also, invention relates to a pharmaceutical composition based on compounds of the invention and to using these compounds. Proposed compounds can be used in treatment of pain being firstly in case of nephropathic or chronic pains.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 421 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

The invention relates to the use of compounds of the type of retinoids as active agents in cosmetic compositions or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors PPK and/or hypervitaminosis A

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of compounds of general formula

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2СН2NH2.

, , .

Claimed method includes interaction of 2-hydroxy-2-cyanoadamantane with ammonia or derivatives thereof such as piperidine, piperazine, 1,2-diaminoethane, etc, in ethanol medium, at 20-80°C for 8-72 h.

EFFECT: enhanced assortment of adamantine derivatives useful as synthetic intermediates for bioactive compounds, method of increased yield.

1 cl, 10 ex

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

< / BR>
< / BR>
< / BR>
which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

Dpp-iv inhibitors // 2345067

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of general formula (I) Z-C(R1R2)-C(R3NH2)-C(R4R5)-X-N(R6R7) (I), or its pharmaceutically acceptable salt which is different because Z represents phenyl; where Z can be substituted with one or more R8, where R8 represents halogen; R1, R4 represent H; R2, R5 represent H; R3 represents H; X is selected from group consisting of S(O)2 and C(O); R6, R7 are independently selected from group consisting of H, (C(R29R30))m-X1-Z1 and (C(R31R32))n-X2-X3-Z2 and C1-4alkyl, which carries substitution with one or more R29a, where R29a is independently selected from group consisting of R29b and Z1, on condition that R6 and R7 are selected in such way that R6 and R7 were not simultaneously independently selected from group consisting of H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2; R29 R29b, R30, R31, R32 are independently selected from group consisting of H, C1-6alkyl and N(R32a)-C1-6alkyl; R32a represents C1-6alkyl; m is 0, 1 or 2; n is 2; X1 is independently selected from group consisting of covalent bond, -C1-6alkyl and -C1-6alkyl-N(R33)-; X2 represents -N(R35)-; X3 represents -C(O)-; R33 represents C1-6alkyl; R35 represents H; Z1, Z2 are independently selected from group consisting of Z3 and -C(R37a)Z3aZ3b; R37a represents H; Z3, Z3a, Z3b are independently selected from group consisting of T1, T2, C1-6alkyl, C1-6alkyl-T1 and C1-6alkyl-T2; T1 represents phenyl; where T1 is optionally substituted with one or more R38; R38 being independently selected from group consisting of halogen, CN, R39, C(O)NH2, S(O)2NH2, OT3, C(O)N(R40)T3 and T3, T2 is selected from group consisting of C3-7cycloalkyl, indanyl, tetralinyl, heterocycle and heterobicycle, T2 optionally carries substitution with one or more R41, where R41 is independently selected from group consisting of halogen, R42, OH and T3; R39 is selected from group consisting of C1-6alkyl, O-C1-6alkyl, S-C1-6alkyl, C(O)N(R44)-C1-6alkyl, S(O)-C1-6alkyl and S(O)2-C1-6alkyl, where each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F, N(R46R47) and T3; R42 represents C1-6alkyl, each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F; R40, R46, R47 are independently selected from group consisting of H and C1-6alkyl; R44 represents H; T3 is selected from group consisting of T4 and T5; T4 represents phenyl, where T4 optionally carries substitution with one or more R51, where R51 is independently selected from group consisting of halogen, OR52, S(O)2N(R52R53), C1-6alkyl; R52, R53 are independently selected from group consisting of H and C1-6alkyl; T5 is selected from group consisting of heretocycle C3-7cycloalkyl, where T5 optionally carries substitution with one or more R54, where R54 represents C1-6alkyl; where heterocycle represents ring of cyclobutane, cyclopentane, cyclohexane, which can contain double bonds in number up to maximal, or aromatic or non-aromatic ring which is fully or partially saturated or unsaturated, and in which at least one carbon atom, maximally up to four carbon atoms, are substituted with heteroatom, selected from group including oxygen and nitrogen, and where ring is bound with remaining part of molecule through carbon or nitrogen atom; where heterobicycle represents heterocycle as stated above, which is condensed with phenyl or other heterocycle with formation of bicyclic ring system, on condition that the following compound is excluded from claim:3-amino-N-cyclohexyl-4-phenylbutyramide. Invention also relates to pharmaceutical composition based on compound of general formula (I) and to their application for manufacturing medication for treatment and/or prevention of conditions during which it is desirable to inhibit DPP-IV.

EFFECT: obtaining novel group of compounds possessing useful biological properties.

26 cl, 8 tbl, 193 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to parecoxib sodium salt in crystalline form that possesses properties of selective inhibitor of cyclooxygenase-2 (COX-2) and can be used in treatment of, for example, inflammatory diseases and pain. Proposed crystalline forms show characteristic peaks of powder X-roentgenogram obtained with using Cu-source of radiation and expressed as angles 2θ and chosen from groups consisting of at least values 5.6; 9.6; 11.0 and 14.5 ± 0.2 angle (form A), and 4.2; 8.3; 12.4; 16.7; 17.5; 20.8 and 24.7 ± 0.2 angle (form B), and 8.8; 11.3; 15.6; 22.4; 23.5 and 26.4 ± 0.2 angle (form E) and wherein each form is anhydrous and non-solvated. Also, invention relates to a method for preparing crystalline form A and to a pharmaceutical composition.

EFFECT: improved preparing method, valuable properties of drug.

21 cl, 5 tbl, 12 dwg, 1 sch, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of aromatic sulfonyl halides by interaction of substituted phenolic compound with halogensulfonic acid and trifluoroacetic acid. Also, invention involves a method for synthesis of 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide of the formula (1) that is useful in treatment of disorders associated with cyclooxygenase-2 and involves interaction of a precursor-compound chosen from group consisting of compounds of the formula (2) and formula (3) with halogensulfonic acid in the presence of trifluoroacetic acid to yield a halogensulfonated compound, and interaction of a halogensulfonated compound with ammonium source to yield compound (isoxazol-4-yl)-benzenesulfonamide of the structural formula (1).

EFFECT: improved method of synthesis.

147 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

The invention relates to new substituted the isoxazoles of General formulas I, II, III, IV, V, where R1selected from lower alkyl, carboxyamide, alkoxycarbonyl, aminocarbonyl, aminocarbonylmethyl and so on; R2choose from alkylsulfonyl, hydroxysulfonic and aminosulfonyl; R3selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from alkyl, cyano, halogenoalkane, hydroxyalkyl and so on; provided that R2is aminosulfonyl, if R2- substituted phenyl radical is in the 3-position isoxazol; R4selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyethyl and so on; R5selected from methyl, hydroxy and amino; R6selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from lower alkylsulfonyl, lower alkyl, cyano, lower halogenoalkane and so on; R7selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyl and so on; R8represents one or more radicals and so on

FIELD: chemistry.

SUBSTANCE: new production method of 2-phenyl-1,2,3-triazole using glyoxal phenylosazone ring formation with new triflate copper catalyst Cu(OSO2CF3)2, both without solvent in melt at 130°C and in high-boiling solvent mediums (toluene, o-xylene, butanol) at boiling temperatures. End product is extracted with high yield column chromatography.

EFFECT: development of new production method of 2-phenyl-1,2,3-triazole.

3 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

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